Pharmaceutical compositions and method for administering 3 and 4-substituted 2(5H)-furanones to a mammal for inhibiting bone loss

ABSTRACT

3 and 4-substituted 2(5H)-furanone compounds influence the balance between bone production and bone resorption in mammals, including humans. The active compounds are administered to mammals, including humans, in an effective dose which ranges between 0.05 to 100 mg per kilogram, body weight, per day, for the purpose of influencing the balance between bone production and bone resorption, and particularly for treating osteoporosis.

CROSS-REFERENCE TO RELATED APPLICATION

The present application is a divisional of application Ser. No.07/872,308, filed on Apr. 24, 1992, now U.S. Pat. No. 5,268,387.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is directed to pharmaceutical compositionscomprising as active ingredients one or more 3- and 4-substituted2(5H)-furanone compounds, and methods for administering suchcompositions to mammals, including humans, for the purpose of inhibitingbone loss.

2. Brief Description of the Prior Art

Osteoporosis is a disease which manifests itself in a decrease of bonedensity throughout the body. The descreased bone density is due to lossof calcium containing bone mineral and also due to loss of bone matrix(collagen). The disease of osteoporosis usually afflicts elderlypatients, more frequently post menopausal women, although beyond the ageof 80 the frequency of the disease is about the same in men as in women.The cause of osteoporosis is not well understood, nevertheless it isbelieved that bone is continuously formed and resorbed during the lifeof a mammal, including human, and that in persons suffering fromosteoporosis the rate of bone resorption is faster than the rate of boneformation, resulting in a net loss of bone density. Thus, osteoporosisis a disease where the balance between bone production and resorption,especially the balance of deposit and resorption of calcium in the bone,is disturbed.

The present methods for treating osteoporosis include physical therapy,administration of anabolic agents, drugs containing phosphorous, vitaminD, calcium salts, fluoride salts calcitonin, and of the antibioticmithramycin. In post-menopausal women estrogen replacement therapy isalso employed to prevent or lessen bone loss.

Among the foregoing, mithramycin is believed to decrease the rate ofbone desorption, and thus modify the balance between bone production andresorption. The prior art which is believed to be closest to the presentinvention is U.S. Pat. No. 4,916,241 describing certain5-hydroxy-2(5H)-furanone derivatives which are substituted in the 4position with a substituted phenyl-methyl, substitutedphenylhydroxymethyl, substituted phenyl alkyl, or with substitutedphenyl-hydroxyalkyl groups, and which modify the balance between boneproduction and bone resorption in a host animal, including man.

As further background to the present invention, it is noted that severaltypes of 4-substituted 2(5H)-furanone derivatives, especially4-substituted 5-hydroxy-2(5H)-furanone derivatives, and certain 3substituted 2(5H)-furanones as well, have been discovered and disclosedin the prior art to be anti-inflammatory, calcium channel blockingand/or antiproliferative agents. However, to the best knowledge of thepresent inventor the only disclosure of4-substituted-5-hydroxy-2(5H)-furanone compounds as agents for modifyingthe balance between bone production and bone resorption is in theabove-noted U.S. Pat. No. 4,916,241 reference.

Unfortunately, none of the known methods for treatment of osteoporosis,or more broadly speaking, methods for favorably modifying the balancebetween bone production and resorption, are entirely satisfactory.Therefore, the search continues in the art for better and/or additionalagents for inhibiting bone loss. The present invention represents animportant discovery and advance in the art in this regard.

SUMMARY OF THE INVENTION

The present invention covers a method of favorably modifying the balancebetween bone production and bone resorption in a host animal, includinghumans, and thereby inhibiting bone loss by administering certain 3- and4-substituted 2(5H)-furanone and certain 4-substituted5-hydroxy-2(5H)-furanone compounds to the host animal. The presentinvention also covers pharmaceutical compositions adapted foradministration to host animals, including humans, for the purpose ofinhibiting bone loss, such compositions containing an effective amountof one or more of the 4-substituted 2(5H)-furanone and 4-substituted5-hydroxy-2(5H)-furanone compounds referred to above.

Specifically, the compounds which are administered in accordance withthe present invention in a pharmaceutical composition for the purpose ofmodifying the balance between bone production and bone resorption, thatis for inhibiting bone loss, are shown by the following formulae:##STR1##

In Formula 1 and in Formula 2 R₁ is H or alkyl of 1 to 20 carbons,CO--R₁ ^(*) CO--O--R_(1*) CO--NH--R_(1*) or PO(OR_(1*))₂ orPO(OR_(1*))R_(1*) where R_(1*) independently is alkyl of 1 to 20 carbonsor phenyl;

X is long chain alkyl having 5 to 25 carbon atoms, long chain alkyl of 5to 25 carbons substituted with an aryl group, or long chain alkyl of 5to 25 carbons substituted with a fluoro substituted aryl group;

Y is COOH, COOR₂, CONH₂, CONHR₂, CON(R₂)₂, CHO, COR₂ ; COCF₃, COCHF₂,CH═NR₂, CR₂ ═N--R₂, CH═N--NHR₂, CH═N--N(R₂)₂, CH═NOH, CR₂ ═N--OH,CH═NOR₂, CR₂ ═NOR₂, CH₂ OH, CHR₂ OH, C(R₂)₂ OH, CH₂ OR_(2*) CHR₂ OR_(2*)C(R₂)₂ OR_(2*) SO₂ R₂, PO(OR₃)₂, and PS(OR₃)₂, where R₂ independently islower alkyl or phenyl, R_(2*) is lower alkyl, phenyl, alkanoyl having 1to 6 carbons, or aroyl, and R₃ is H, lower alkyl, or phenyl;

W is H, lower alkyl, phenyl, COOH, COOR₄, CONHR₄, CON(R₄)₂ where R₄ islower alkyl, and

Z is H or alkyl. ##STR2##

In Formula 3 R₁ is H or alkyl of 1 to 20 carbons, CO--R_(1*)CO--O--R_(1*) CO--NH--R_(1*) or PO(OR_(1*))₂ or PO(OR_(1*))R_(1*) whereR_(1*) independently is alkyl of 1 to 20 carbons, or phenyl with theproviso that when R₁ is CO--NH--R_(1*) then R_(1*) is not H;

X is O, S, SO--, SO₂, NH--, or NR₂ where R₂ is phenyl, or alkyl of 1 to20 carbons, and

Y is alkyl of 6 carbon atoms, aryl C₁ -C₆ alkyl, aryl, alkenylcontaining one or more olephinic bonds and 6 to 25 carbon atoms, CO--R₃,CO--OR₃, CONHR₃, SO₂ R₃, SO₂ NHR₃ where R₃ is aryl, alkyl of 4 to 25carbons, alkenyl of 4 to 25 carbons containing one or more olephinicbonds, further Y is (CH₂)_(n) --O--R₄, or (CH₂)_(n) --O--(CH₂)_(m)--O--R₄, where n, and m, are integers and are independently 1 to 25 andR₄ is phenyl or alkyl of one to 20 carbons, still further Y is PO(OH)₂,PO(OH)OR₅, PO(OH)R₅ PO(OR₅)₂, where R₅ is independently phenyl, alkyl of1 to 20 carbons or R₅ is (CH₂)_(n) --N(R_(5*))₃ where R_(5*) is alkyl of1 to 20 carbons, or Y is NH--R₆ where R₆ is phenyl, or alkyl of 6 to 25carbon atoms with the proviso that when X is O, S, then Y is not NH--R₆,and with the further proviso that when X is SO or SO₂ then Y is not SO₂R₃ or SO₂ NHR₃. ##STR3##

In Formula 4 R' is H or lower alkyl of 1 to 6 carbons;

R is alkyl having 4 to 25 carbons, carbocyclic arylalkyl or alkenylcontaining 4 to 25 carbons and one or more olephinic bonds;

X is O, NH or NR₁, where R₁ is alkyl of 1 to 20 carbons or arylalkyl;

Y is H, alkyl of 1 to 20 carbons, carbocyclic arylalkyl, carbocyclicaryl, alkenyl containing one or more olephinic bonds and 2 to 20carbons, PO(OH)₂, PO(OH)OR₂, PO(OH)R₂ PO(OR₂)₂, where R₂ isindependently alkyl of 1 to 20 carbons or phenyl, further Y is CO--R₃,CO--OR₃, CONHR₃, SO₂ R₃, SO₂ NHR₃, (CH₂)_(n) --O--R₃, or (CH₂)_(n)--O--(CH₂)_(m) --O--R₃, where n, and m, are integers and areindependently 1 to 20 and R₃ is H, alkyl having 1 to 6 carbons, alkenylcontaining one or more olephinic bonds and 2 to 6 carbons, carbocyclicaryl, carbocyclic arylalkyl, with the proviso that when Y is CO--R₃, andCONHR₃ then R₃ is not hydrogen. ##STR4##

In Formula 5 R is C₇ -C₂₀ alkyl;

R₁ is OCOR₂, 2-(methoxy)ethoxymethoxy, halogen and NHR₃ ;

R₃ is H, C₁ -C₆ alkanoyl, COCF₃ and C₁ -C₆ sulfonyl;

R₂ is C₁ -C₁₄ alkyl or amino N-substituted by one α-(C₁ -C₄ alkyl)benzylgroup, by one or two C₁ -C₄ alkyl groups or by one phenyl group; orOP(R₄ R₅); or

R is 2-(methoxy)ethoxymethoxymethyl and R₁ is OCO--(C₇ -C₁₄ alkyl); or

R is CH(OCOC₁ -C₄ alkyl)C₇ -C₂₀ alkyl and R₁ is OCO(C₁ -C₄ lkyl); and

R₄ =R₅ is H or C₁ -C₄ alkyl. ##STR5##

In Formula 6 A is CH₂ --CO₂ M, CH₂ CH₂ OCOR, (CH₂)_(n) CH═CHCOR,(CH₂)_(q) COR, ##STR6## n is 1 or 2; q is 1-4;

m is 8-12;

R is C₇ -C₁₄ alkyl, C₇ -C₁₄ alkoxide, NR₃ (CH₂)_(p) Z or C═CM;

p is2-8;

Z is H, N(R₃)₂ or CO₂ H;

R₁ is hydrogen or C₁ -C₄ alkyl;

R₂ is C₇ -C₁₄ alkyl or phenyl;

M is C₇ -C₁₄ alkyl; phenyl(C₁ -C₄ alkyl) optionally substituted on thephenyl ring by 1-3 halo substituents; pyridyl (C₁ -C₄ alkyl) or naphthyl(C₁ -C₆ alkyl);

R₄ is O----(C₈ -C₁₄ alkyl) or NH(C₈ -C₁₄ alkyl); and R₅ is hydrogen orR₄ is OH and R₅ is o-hydroxyphenyl;

X is hydrogen, acetyl, PO(OH)₂ or CO(CH₂)₃ N(R₃)₂.HCl;

R₃ is C₁ -C₄ alkyl and

R₆ is phenyl or C₄ -C₁₂ alkyl, and

Y is C₁ -C₆ alkanoyl. ##STR7##

In Formula 7 R₁ is H or alkyl of 1 to 20 carbons, CO--R_(1*)CO--O--R_(1*) CO--NH--R_(1*) or PO(OR_(1*))₂ or PO(OR_(1*))R_(1*) whereR_(1*) independently is H, alkyl of 1 to 20 carbons, or phenyl;

R₂ is H or alkyl of 1 to 20 carbons;

X is H, R₃, CO--R₃, CO--O--R₃, CO--NH--R₃, CO--N--(R₃)₂, PO(OR₃)₂ orPO(OR₃)R₃, and R₃ independently is H, phenyl, alkyl of 1 to 20 carbonsor is alkyl of 1 to 20 carbons substituted with a hydroxyl, alkoxy,amino, thioalkoxy or with a COR_(3*) group where R_(3*) is H, loweralkyl, OH, OR_(3**), NH₂, NHR_(3**) or N(R_(3**))₂ group where R_(3**)independently is H or lower alkyl, with the proviso that when X isCO--O--R₃ or is CO--NH--R₃ then R₃ is not hydrogen;

Y is H, R₄, CO--R₄, CO--O--R₄, CO--N-piperazinyl, CO--N-substituted N--piperazinyl, CO--N-morpholinyl, CO--N-substituted N-morpholinyl,CO--NH--R₄, or CO--N(R₄)₂, PO(OR₄)₂, PO(OR₄)R₄, SO₂ OR₄, or SO₂ R₄,where R₄ independently is H, phenyl, phenyl substituted with twocarboxyl groups, alkyl of 1 to 20 carbons, or is alkyl of 1 to 20carbons substituted with a hydroxyl, alkoxy, dialkyl substituted amino,thioalkoxy, with a COR_(4*) or with a O--COR_(4*) group where R_(4*) isH, lower alkyl, OH, OR_(4**), NH₂, NHR_(4**) or N(R_(4*))₂ group whereR_(4**) is lower alkyl with the proviso that when Y is CO--O--R₄ then R₄is not hydrogen. ##STR8##

In Formula 8 and in Formula 9 R₁ is H or alkyl of 1 to 20 carbons,CO--R_(1*) CO--O--R_(1*) CO--NH--R_(1*) or PO(OR_(1*))₂ orPO(OR_(1*))R_(1*) where R_(1*) independently is H, alkyl of 1 to 20carbons, or phenyl;

R₂ is H, alkyl of 1 to 20 carbons, or R₂ and Y jointly represent aheterocycle which incorporates the sulfonamide nitrogen in the ring as aheteroatom;

R₃ is H or alkyl of 1 to 20 carbons;

X is H, R₄, CO--R₄, CO--O--R₄, CO--NH--R₄, CO--N--(R₄)₂, PO(OR₄)₂ orPO(OR₄)R₄, and R₄ independently is H, phenyl, alkyl of 1 to 20 carbonsor is alkyl of 1 to 20 carbons substituted with a hydroxyl, alkoxy,amino, thioalkoxy, with a O--COR_(4*) group or with a COR_(4*) groupwhere R_(4*) is H, lower alkyl, OH, OR_(4**), NH₂, NHR_(4**) orN(R_(4**))₂ group where R_(4**) independently is H or lower alkyl, withthe proviso that when X is CO--O--R₄ or is CO--NH--R₄ then R₄ is nothydrogen;

Y is H, phenyl or carboxy substituted phenyl, or alkyl of 1 to 20carbons, or is alkyl of 1 to 20 carbons substituted with a hydroxyl,alkoxy, dimethyl substituted amino, thioalkoxy, O--PO(OR₅)₂,O--PO(OR₅)R₅, O--SO₃ H, O--SO₂ R₅, O--COR₅, or COR₅ group where R₅ is H,lower alkyl, OH, OR_(5*), NH₂, NHR_(5**) or N(R_(5*))₂ group whereR_(5*) is lower alkyl, or R₂ and Y jointly represent a heterocycle whichincorporates the sulfonamide nitrogen in the ring as a heteroatom, withthe proviso that when Y is an alkyl substituted with O--PO(OR₅)₂ or withO--PO(OR₅)₅ then R₅ is not OH. ##STR9##

In Formula 10 R is hydrogen, C₁ -C₆ alkanoyl, C₁ -C₆ carbamoyl, phenylcarbamoyl, C₁ -C₆ dialkylphosphonate or PO(OH)₂ ;

R₁ is halo,

NHCOR₃,

NHSO₂ R₈,

NHPO(OCH₃)CH₃ ;

OCOR₄,

OR₅ or

S(O)_(m) R₈ ;

SCOCH₃ ;

OCONH-phenyl;

OCO--N(CH₃)CONH(CH₃)

R₂ is C₈ -C₂₀ alkyl;

R₃ is C₁ -C₄ alkyl, C₁ -C₄ alkoxy, trifluoromethyl, ----(CH₂)₃ ----COOH,NHR₈ or N----R₉ R₁₀ ;

R₄ is C₁ -C₄ alkoxy, phenoxy, R₆ -(C₁ -C₄ alkyl), or NHSO₂ N(C₂ H₅)₂ ;R₅ is C₈ -C₂₀ alkyl, phenyl, 2-methoxyethyl, 2-(methoxy) ethoxymethyl,t-butyl dimethylsilyl, PO(OR₇)R₈ or PS(OR₇)R₈ ;

R₆ is carboxy, C₁ -C₄ alkoxycarbonyl, halo or CONR₁₁ R₁₁ ;

R₇ is hydrogen or C₁ -C₄ alkyl or phenyl;

R₈ is C₁ -C₄ alkyl, ethoxy, hydroxy, hydrogen or C₁ -C₆ alkanoyl;

R₉ is H or C₁ -C₄ alkyl;

R₁₀ is H, C₁ -C₄ alkyl or SO₂ NR₂ R₂ ;

R₁₁ is H or C₁ -C₄ alkyl; and

m is 0-2. ##STR10##

In Formula 11 the dotted line represents absence of a bond or a singlebond;

R₁ is hydrogen, C₁ -C₄ alkyl, benzyl, C₁ -C₂₀ alkanoyl, cyclohexanoyl,benzoyl, phenyl (C₁₋₄ alkanoyl) or naphthoyl;

Z is --C(OR₂)H--;

R₂ is H, C₁ -C₄ alkyl, C₁ -C₂₀ alkanoyl, trihaloacetyl, cyclohexanoyl,benzoyl, phenyl(C₁₋₄ alkanoyl), phenyl(C₂ -C₁₄ alkenoyl), naphthoyl, orcarbamoyl optionally N-substituted by one or two C₁₋₄ alkyl groups or byone alpha-(C₁ -C₄ alkyl)benzyl group;

R₃ is hydrogen, C₁ -C₂₀ straight chain alkyl, phenyl(C₁ -C₂₀ straightchain alkyl or alkenyl of 1-6 unconjugated double bonds), cyclohexyl(C₁-C₂₀ straight chain alkyl or alkenyl having 1-6 unconjugated doublebonds), phenyl, cyclohexyl or benzothienyl(C₁ -C₂₀ alkyl or alkenylhaving 1-6 unconjugated double bonds), 4-methyl-3-pentenyl,4-methyl-6-(2,6,6-trimethyl-cyclohex-1-enyl)hex-3-enyl,1-(2-ethenyl)-1,5,9-trimethyl-deca-4,8-dienyl, Y-(CH₂)_(n) orB-(straight chain C₃ -C₁₄ alkynyl);

R₄ is hydrogen, bromo or chloro but is not bromo or chloro when R₃contains a double bond;

n is 6-12;

Y is OR₅, CO₂ R₆, t-butyl, t-butyldimethylsilyl, diphenylmethyl,triphenylmethyl, pyridyl, thienyl, quinolyl, N--C₁ -C₄ alkylpyrrolyl,N--C₁ -C₄ alkylpiperidyl, N--C₁ -C₄ alkylpyridinium halide or naphthyl;

R₅ is hydrogen, C₁ -C₄ alkyl or C₁ -C₄ alkanoyl;

R₆ is hydrogen or C₁ -C₄ alkyl;

B is hydrogen, phenyl, pyridyl or naphthyl;

and a lactone formed when R₂ is hydrogen and R₃ is (CH₂)₁₁₋₁₅ COOH; saidphenyl in the definition of R₃ being optionally substituted by C₁ -C₁₄alkyl, alkenyl, alkynyl or aryl, CO₂ R₆, C₁ -C₄ alkoxy or halo.##STR11##

In Formula 12 R₁ is hydrogen or C₁ -C₂₀ alkanoyl, and

R₃ is C₅ -C₂₀ straight chain alkyl, benzothienyl(C₁ -C₂₀ alkyl),4-methyl-3-pentenyl,4-methyl-6-(2,6,6-trimethylcyclohex-1-enyl)hex-3-enyl or1-(2-ethenyl)-1,5,9-trimethyldeca-4,8-dienyl. ##STR12##

In Formula 13 R₁ is hydrogen, C₁ -C₄ alkyl, benzyl, C₁ -C₂₀ alkanoyl,cyclohexanoyl, benzoyl, pheny(C₁₋₄ alkanoyl) or naphthoyl;

R₃ is H, C₁ -C₂₀ straight chain alkyl, phenyl(C₁ -C₂₀ straight chainalkyl), cyclohexyl(C₁ -C₂₀ straight chain alkyl), phenyl, cyclohexyl orbenzothienyl(C₁ -C₂₀ alkyl), 4-methyl-3-pentenyl,4-methyl-6-(2,6,6-trimethylcyclohex-1-enyl)hex-3-enyl,1-(2-ethenyl)-1,5,9-trimethyldeca-4,8-dienyl, Y-(CH₂)_(n) or B-(straightchain C₃ -C₁₄ alkynyl);

R₄ is hydrogen, bromo, or chloro but is not bromo or chloro when R₃contains a double bond;

n is 6-12;

Y is OR₅, CO₂ R₆, t-butyl, t-butyldimethylsilyl, diphenylmethyl,triphenylmethyl, pyridyl, thienyl, quinolyl, N--C₁ -C₄ alkylpyrrolyl,N--C₁ -C₄ alkylpiperidyl, N--C₁ -C₄ alkylpyridinium halide or naphthyl;

R₅ is hydrogen, C₁ -C₄ alkyl or C₁ -C₄ alkanoyl;

R₆ is hydrogen or C₁ -C₄ alkyl;

B is hydrogen, phenyl, pyridyl or naphthyl. ##STR13##

In Formula 14 R₂₀ is hydrogen, C₁ -C₁₄ alkanoyl, COHNR₂₃ or CO₂ R₂₄ ;

R₂₃ is phenyl or C₁ -C₄ alkyl;

R₂₄ is C₁ -C₆ alkyl;

A is CH₂ O--R₂₁ or CH(C₇ -C₁₄ alkyl); or OCOR₂₂

when R₂₀ is C₁ -C₁₄ alkanoyl, A may be CH₂ OCOR₂₂ or CH₂ OP(O)(OR₂₂)R₂₂;

R₂₁ is C₇ -C₁₄ alkanoyl, N--(C₆ -C₁₄ alkyl) carbamoyl, naphthyl-(C₁ -C₆alkyl), pyridyl-(C₁ -C₆ alkyl) or methoxyethoxymethoxymethyl;

R₂₂ is C₁ -C₄ alkyl; and

R₂₅ is H, C₁₋₆ alkanoyl or C₁₋₆ alkyl. ##STR14##

In Formula 15 R₁ is phenyl (C₁₋₁₇ alkyl or alkenyl having 1-5unconjugated double bonds), benzothienyl (C₁₋₁₇ alkyl or alkenyl having1-5 unconjugated double bonds);

R₂ is hydrogen or a C₁₋₄ alkyl group, and

Y is H, or C₁ -C₆ alkanoyl. ##STR15##

In Formula 16 R₁ is alkyl or alkenyl having 1-5 unconjugated doublebonds, phenyl (C₁ -C17 alkyl or alkenyl having 1-5 unconjugated doublebonds), benzothienyl (C₁₁ -17 alkyl or alkenyl having 1-5 unconjugateddouble bonds), naphthyl (C₁ -C₁₇ alkyl or alkenyl having 1-5unconjugated double bonds), cyclohexyl or methyl;

R₃ is hydrogen or C₁ -C₄ alkanoyl; and

Y is H or C₁ -C₆ alkanoyl. ##STR16##

In Formula 17 R₁ is H, alkyl of 1 to 20 carbons, alkylene having one ormore double bonds, alkyne having one or more triple bonds, arylalkyl,arylalkylene having one or more double bonds, or arylalkyne having oneor more triple bonds;

R₂ is H, alkyl of 1 to 20 carbons, alkylene having one or more doublebonds, alkyne having one or more triple bonds, arylalkyl, arylalkylenehaving one or more double bonds or arylalkyne having one or more triplebonds, and

R₃ is H, alkyl of 1 to 20 carbons, arylalkyl, or halogene. ##STR17##

In Formula 18 R₁ is H, alkyl of 1 to 20 carbons, alkylene having one ormore double bonds, alkyne having one or more triple bonds, arylalkyl,arylalkylene having one or more double bonds, or arylalkyne having oneor more triple bonds;

R₂ is H, alkyl of 1 to 20 carbons, alkylene having one or more doublebonds, alkyne having one or more triple bonds, arylalkylene having oneor more double bonds or arylalkyne having one or more triple bonds;

R₃ is H, alkyl of 1 to 20 carbons, arylalkyl, or halogene, and

X is H or alkyl of 1 to 20 carbons, CO--X*, CO--O--X*,, CO--NH--X*,, orPO(OX*,)₂ or PO(OX*,)X*,, where X*, independently is H, alkyl of 1 to 20carbons, phenyl, or substituted phenyl, with the proviso that R₁ and R₃both are not hydrogen. ##STR18##

In Formula 19a and 19b R₁ independently is H, phenyl, C₁ -C₆ alkylsubstituted phenyl, halogen substituted phenyl, or alkyl of 1 to 6carbons and n is an integer having the values of 1 or 2, and where whenn is 1 the R₁ group is attached to one of the 3 and the 5 positions ofthe 2-furanone, when n is 2 then the R₁ groups are attached to both the3 and 5 positions with the proviso that when n is 1 then R₁ is not H;

Y₁ is H, alkyl of 1 to 20 carbons, phenyl C₁ -C₂₀ alkyl, C₁ -C₂₀ alkenylcontaining one or more olephinic bonds, PO(OH)₂, PO(OH)OR₂, PO(OH)R₂,PO(OR₂)₂, where R₂ is independently alkyl of 1 to 20 carbons, phenyl, orhalogen substituted phenyl, or C₁ -C₆ alkyl substituted phenyl, furtherY₁ is CO--R₃, CO--OR₃, CONHR₃, SO₂ R₃, SO₂ NHR₃, (CH₂)_(p) --O--R₃, or(CH₂)_(p) --O--(CH₂)_(m) --O--R₃, where p, and m, are integers and areindependently 1 to 20 and R₃ is H, C₁ -C₂₀ alkyl, C₁ -C₂₀ alkenylcontaining one or more olephinic bonds, phenyl, halogen substitutedphenyl, or C₁ -C₆ alkyl substituted phenyl, with the proviso that whenY₁ is CO--R₃, CO--OR₃ , and CONHR₃ then R₃ is not hydrogen;

Y₂ is an alkyl group of 6 to 25 carbons, phenyl, naphthyl, phenyl (C₁-C₂₀)alkyl-, naphthyl (C₁ -C₂₀)alkyl-, C₁ -C₆ alkyl substituted phenyl,halogen substituted naphthyl, C₁ -C₆ substituted naphthyl, and

Y₃ is H, alkyl of 1 to 20 carbons, CO--R₄, CO--O--R₄, CO--NH--R₄,PO(OR₄)₂ or PO(OR₄)R₄, where R₄ independently is H, alkyl of 1 to 20carbons, phenyl, or halogen substituted phenyl, or C₁ -C₆ alkylsubstituted phenyl, with the proviso that when Y₃ is COOR₄ then R₄ isnot H. ##STR19##

In Formula 20a and 20b R₁ independently is phenyl or alkyl of 1 to 6carbons, the R₁ groups being attached to the 3 and 5 positions of the2-furanone;

Y₁ is CO--R₃, or CO--NHR₃ and R₃ is C₆ -C₂₀ alkyl, and

Y₃ is H or CO--R₄ where R₄ is alkyl of 1 to 6 carbons. ##STR20##

In Formula 21 R₁ is H, alkyl of 1 to 20 carbons, CO--R₂, CO--O--R₂,CO--NH--R₂, PO(OR₂)₂, or PO(OR₂)R₂, where R₂ independently is H, alkylof 1 to 20 carbons, phenyl, lower alkyl substituted phenyl or halogensubstituted phenyl;

n is an integer between 8 to 14;

Y is H, alkyl having 1-20 carbon atoms, carbocyclic aryl[lower alkyl],carbocyclic aryl, lower alkyl[carbocyclic aryl], alkenyl containing oneor more olephinic bonds and 1-20 carbon atoms, CO--R₃, CO--OR₃, CONHR₃,SO₂ R₃, or SO₂ NHR₃ where R₃ is carbocyclic aryl[lower alkyl],carbocyclic aryl, lower alkyl[carbocyclic aryl], alkenyl containing oneor more olephinic bonds and 1-20 carbon atoms, further Y is PO(OH)₂,PO(OH)OR₄, PO(OH)R₄, or PO(OR₄)₂, where R₄ is independently alkyl of1-20 carbons or phenyl. ##STR21##

In Formula 22 R₁ independently is H or alkyl of 1 to 20 carbons, CO--R₂,CO--O--R₂, CO--NH--R₂, or PO(OR₂)₂ or PO(OR₂)R₂, where R₂ independentlyis H, alkyl of 1 to 20 carbons, phenyl, or lower alkyl substitutedphenyl or halogen substituted phenyl;

A is (CH₂)_(n) where n ranges between 0 to 30, or A is a a divalentbranch chained alkyl radical, or cycloalkyl radical, having a total of 3to 30 carbons;

R₃ independently is an alkyl group having 4 to 20 carbons, and

X is O or NH. ##STR22##

In Formula 23 R₁ independently is H or alkyl of 1 to 20 carbons, CO--R₂,CO--O--R₂, CO--NH--R₂, or PO(OR₂)₂ or PO(OR₂)R₂, where R₂ independentlyis H, alkyl of 1 to 20 carbons, phenyl, or lower alkyl substitutedphenyl or halogen substituted phenyl;

A is (CH₂)_(n) where n ranges between 5 to 30, or A is a a divalentbranch chained alkyl radical, or cycloalkyl radical, having a total of 5to 30 carbons, and

X is O or NH.

Pharmaceutically acceptable salts of the compounds shown by Formulae 1through 23 can also be administered in accordance with the method oftreatment of the present invention.

GENERAL EMBODIMENTS Definitions

The terms "ester", "amine", "amide", "ether" and all other terms andterminology used here, (unless specifically defined in the presentdescription) refer to and cover any compounds falling within therespective term as that term is classically used in organic chemistry.

Unless specifically noted otherwise, preferred esters are derived fromthe saturated aliphatic alcohols or acids of ten or fewer carbon atomsor from the cyclic or saturated aliphatic cyclic alcohols and acids of 5to 10 carbon atoms. Particularly preferred aliphatic esters are thosederived from lower alkyl acids or alcohols. Also preferred are thephenyl or lower alkylphenyl esters.

The term "alkyl" as used in the present description and claims includesstraight chain alkyl groups, branched chain alkyl groups, cycloalkylgroups, alkyl substituted cycloalkyl groups, and cycloalkyl substitutedalkyl groups. Unless the number of carbons is otherwise specified,"lower alkyl" means the former broad definition of "alkyl" groups butwith the restriction that the group has 1 to 6 carbon atoms.

Unless specifically noted otherwise, the term "long chain alkyl" alsomeans the former broad definition of "alkyl" groups but with therestriction that the group has no less than 4 carbon atoms, and no morethan approximately 25 carbon atoms.

Unless specifically noted otherwise, preferred amides are the mono- anddi-substituted amides derived from the saturated aliphatic radicals often or fewer carbon atoms, or the cyclic or saturated aliphatic-cyclicradicals of 5 to 10 carbon atoms.

Some of the compounds utilized in the method and pharmaceuticalcomposition of the invention may contain one or more chiral centers.Accordingly, these compounds may be prepared as mixtures of enantiomericcompounds (where the enatiomers may or may not be present in equalamounts) or as optically pure enantiomers. When there is more than onechiral center, the compounds may also be prepared as mixtures ofdiastereomers, or as pure diastereomers, and each diastereomer itselfmay be a mixture of enantiomers in 1:1, or other, ratios. Alternatively,each diastereomeric compound may be sterically and optically pure.However, all of the above-noted forms, including optically pureenantiomers and mixtures thereof, as well as all diastereomers, arewithin scope of the present invention.

Some of the compounds utilized in the method and pharmaceuticalcomposition of the invention may have cis and trans stereoisomers. Thescope of the invention includes the use of both pure stereoisomers aswell as mixtures thereof.

A pharmaceutically acceptable salt of any compound shown by Formulae1-23 may be prepared and used in the method of the present inventionprovided the compound has a functionality capable of forming such salt,for example an acid or an amine functionality. A pharmaceuticallyacceptable salt may be any salt which retains the activity of the parentcompound and does not impart any deleterious or untoward effect on thesubject to which it is administered and in the context in which it isadministered.

Such a salt may be derived from any organic or inorganic acid or base.The salt may be a mono or polyvalent ion. Of particular interest wherethe acid function is concerned are the inorganic ions, sodium,potassium, calcium, and magnesium. Organic amine salts may be made withamines, particularly ammonium salts such as mono-, di- and trialkylamines or ethanol amines. Salts may also be formed with caffeine,tromethamine and similar molecules. Where there is a nitrogensufficiently basic as to be capable of forming acid addition salts, suchmay be formed with any inorganic or organic acids or alkylating agentsuch as methyl iodide. Preferred salts are those formed with inorganicacids such as hydrochloric acid, sulfuric acid or phosphoric acid. Anyof a number of simple organic acids such as mono-, di- or tri-acid mayalso be used.

The compounds shown by Formulae 1-23 (or their pharmaceuticallyacceptable salts) are utilized, in accordance with the presentinvention, for treating animals of the mammalian species (includinghumans) for the purpose of modifying the balance between bone productionand resorption, namely for the purpose of inhibiting or decreasing therate of undesirable bone loss. Osteoporosis is a disease which ischaracterized by undesirable bone loss. Thus, the compounds shown byFormulae 1-23 (or their pharmaceutically acceptable salts) can be used,in accordance with the present invention, for treating osteoporosis.

The capacity of the compounds utilized in the method of the presentinvention to modify the balance of bone production and bone resorption,can be evaluated essentially as is described by G. Eilon and l. G.Raisz: "Comparison of the effects of stimulators and inhibitors ofresorption on the release of lysosomal enzymes and radioactive calciumfrom fetal bone in organ culture" Endocrinology 103:1969-1975 (1978).For further description of assay procedures suitable for evaluatinginhibition of bone loss by the compounds utilized in accordance with thepresent invention, reference is made to U.S. Pat. No. 4,916,241 (andparticularly to Column 8 line 34 through Column 9 line 56 thereof), andthe specification of U.S. Pat. No. 4,916,241 is expressly incorporatedherein by reference.

The biologically active compounds shown by Formulae 1-23 areadministered in accordance with the present invention to mammals,including humans, in an effective amount to produce the desiredactivity, preferably in an amount of about 0.05 to 100 mg per day perkilogram of body weight. The nature of the host animal, (or person) age,weight and condition and extent of symptoms, as well as the identity ofthe compound used, is likely to affect the actual daily dose, which maybe a single dose, or the compound (or a pharmaceutically acceptable saltthereof) may be administered in multiple doses. Generally speaking,treatment in accordance with the invention may be initiated with a smalldosage, and the dosage may be thereafter increased gradually until thedesired effect, or the optimum effect attainable under thecircumstances, is obtained.

The compounds are admistered in the method of treatment of the inventionin a pharmaceutical composition adapted for standard routes ofadministration. Such pharmaceutical compositions comprise the activecompounds as well as pharmaceutical carriers suitable for the route ofadministration. Standard methods for formulating pharmaceuticalcompositions of this type may be found in Remington's PharmaceuticalSciences, Mack Publishing Company, Easton, Pa.

Although several routes of administration of the compounds of theinvention can be used, the preferred routes of administration are oraland parental.

For oral administration, suitable pharmaceutical carriers includemannitol, lactose, starch, magnesium stearate, talcum, glucose andmagnesium carbonate. Oral compositions may be in the form of tablets,capsules, powders, solutions, suspensions, sustained releaseformulations, and the like.

A typical tablet or capsule may contain the following:

    ______________________________________                                        Ingredients      Percent w/w                                                  ______________________________________                                        Lactose, spray-dried                                                                           40-99                                                        Magnesium stearate                                                                             1-2                                                          Cornstarch       10-20                                                        Active ingredient                                                                              0.001-20                                                     ______________________________________                                    

Parenteral compositions are prepared in conventional suspension orsolution forms, as emulsions or as solid forms for reconstruction.Suitable carriers are water, saline, dextrose, Hank's solution, Ringer'ssolution, glycerol, and the like. Parenteral administration is usuallyby injection which may be subcutaneous, intramuscular or intravenous.

The active compounds used in the method of treatment of this invention,may be combined with other known agents and drugs in the pharmaceuticalcompositions and methods described herein.

SPECIFIC EXAMPLES

The preferred compounds for use in the process of the present inventionare disclosed in connection with the herein described examples. Thesynthetic processes for preparing the compounds utilized in the methodof treatment of the present invention are also disclosed in connectionwith the specific examples. Generally speaking, and with respect to the4-substituted 5-hydroxy 2(5H)-furanone derivatives utilized in themethod of the present invention, the process of their preparationincludes a step where a 2-trialkylsilylfuran intermediate, which has theside chain in the 4 position of the furan nucleus that is desired forbiological activity, is subjected to oxidation by singlet oxygen toprovide the biologically active 4-substituted 5-hydroxy-2-(5H)-furanone.The conditions of the reactions with singlet oxygen are described indetail in connection with several specific examples. In general terms,these oxidation reactions are preferably conducted in a mixture of waterand acetone or in a mixture of water and tetrahydrofuran, and in someinstances in substantially neat tetrahydrofuran, in the presence of aninitiator, preferably Rose Bengal dye (preferably polymer bounded),which is added to the reaction mixture. The reaction mixture and vesselis flushed with oxygen and the reaction is conducted at low temperature,at approximately -78° C., or for the herein described reactionspreferably at approximately 0° C., under a constant positive pressure ofoxygen for a number of hours, typically 1 to 7 hours. The mixture istypically irradiated with a 150 Watt flood lamp. Work-up of the reactionmixture after irradiation usually includes concentration by evaporationof the solvent, followed by chromatography on silica gel, in columns oron preparative silica plates.

Example 1 ##STR23##

The compounds which are preferred in the method of treatment of thepresent invention and which are designated by Formula 1 and Formula 2above, have the following preferred structural features.

With respect to the 5-position of the furanone moiety, those compoundsof Formula 1 and Formula 2 are preferred where the substituent ishydroxy or acetoxy (R₁ is H or CH₃ CO).

With respect to the Z substituent on the beta carbon in the side chain(in the 4-position) of the furanone moiety (Formula 1), the preferredcompounds are those where Z is hydrogen.

With respect to the W substituent on the beta carbon of the side chainin the 4-position of the furanone molecule, the preferred compounds arethose where W is hydrogen, or is COOR₄ (R₄ defined as in Formula 1),preferably R₄ is methyl.

With respect to the X substituent on the alpha carbon of the side chainin the 4-position of the furanone molecule, the preferred compounds arethose where X is long chain alkyl of more than 8 carbons, or X is5-(phenyl)pentyl, or a derivative substituted in the phenyl ring.Particularly preferred in this regard are compounds where X is CH₃(CH₂)₁₁, and compounds where X is 5-(2,4,5-trifluorophenyl)pentyl.

With respect to the Y substituent on the beta carbon of the side chainin the 4-position of the furanone molecule, the preferred compounds arethose where Y is COOH, COOR₂, CONH₂ with R₂ in these ester preferablybeing lower alkyl, most preferably methyl or ethyl. Compounds are alsopreferred where Y is COR₂, COCF₃, COCF₂ H, with R₂ preferably beingmethyl in these ketone compounds. Still further, compounds are preferredwhere Y is CH═NOH, or CH═NOR₂ (aldoximes), CR₂ ═NOH, CR₂ ═NOR₂(ketoximes) and CH═N--NHR₂ (hydrazones) with R₂ preferably being methylin these oxime or hydrazone compounds. Other preferred compounds arewhere Y is C(R₂)₂ OH (tertiary alcohols, with R₂ preferably beingmethyl) and where Y is PO(OR₃)₂, PS(OR₃)₂, SO₂ R₂ (phosphonyl,thiophosphonyl and sulphonyl compounds). The sulphonyl compounds areparticularly preferred where R₂ is methyl, and phosphonyl compounds areparticularly preferred where R₃ is ethyl.

The most preferred compounds of this example, used in accordance withthe method of treatment of the invention are those listed just belowwith reference to Formula 24 or Formula 25: ##STR24##

Formula 24, Compound 1: W═H, X═CH₃ --(CH₂)₁₁ and Y═CO₂ CH₂ CH₃ ;

Formula 24, Compound 2: W═H, X═CH₃ --(CH₂)₁₁ and Y═COCH₃ ;

Formula 24, Compound 3: W═H, X═CH₃ --(CH₂)₁₁ and Y═COCF₃ ;

Formula 24, Compound 4: W═H, X═CH₃ --(CH₂)₁₁ and Y═C(CH₃)₂ OH;

Formula 24, Compound 5: W══CO₂ CH₃, X═CH₃ --(CH₂)₁₁ and Y═CO₂ CH₃ ;

Formula 24, Compound 6: W═H, X═CH₃ --(CH₂)₁₁ and Y═COOH;

Formula 24, Compound 7: W═H, X═CH₃ --(CH₂)₁₁ and Y═PO(OCH₂ CH₃)₂ ;

Formula 24, Compound 8: W═H, X═5-(2,4,5-trifluorophenyl)pentyl

and Y═COCF₃ ;

Formula 24, Compound 9: W═H, X═CH₃ --(CH₂)₁₁ and Y═CH═NOCH₃ ;

Formula 24, Compound 10: W═H, X═CH₃ --(CH₂)₁₁ and Y═CONH₂ ;

Formula 24, Compound 11: W═H, X═CH₃ --(CH₂)₁₁ and Y═CH═NOH;

Formula 24, Compound 12: W═H, X═CH₃ --(CH₂)₁₁ and Y═CH═NNHCH₃ ;

Formula 24, Compound 13: W═H, X═CH₃ --(CH₂)₁₁ and Y═COCF₂ H;

Formula 24, Compound 14: W═H, X═CH₃ --(CH₂)₁₁ and Y═PS(OCH₂ CH₃)₂ ;

Formula 24, Compound 15: W═H, X═CH₃ --(CH₂)₁₁ and Y═SO₂ CH₃ ;

Formula 24, Compound 16: W═H, X═CH₃ --(CH₂)₁₁ and Y═CCH₃ ═NOH;

Formula 25, Compound 17: X═CH₃ --(CH₂)₁₁ and Y═COCF₃, and

Formula 25, Compound 18: X═CH₃ --(CH₂)₁₁ and Y═PO(OCH₂ CH₃)₂ ;

The compounds corresponding to Formula 1, 2, including the preferredcompounds identified above in connection with Formula 24 and Formula 25can be prepared in accordance with the disclosure of U.S. Pat. No.5,013,850, the specification of which is expressly incorporated hereinby reference.

Example 2 ##STR25##

The compounds which are preferred in the method of treatment of thepresent invention and which are designated by Formula 3 above, have thefollowing preferred structural features.

The preferred compounds with reference to Formula 3 and with respect tothe 5-position of the furanone moiety are those where the substituent ishydroxy, acetoxy or alkanoyloxy derived from an alkanoic acid includinga long chain alkyl group (R₁ is H, CH₃ CO, or is CO--R_(1*) where R_(1*)is long chain alkyl). Particularly preferred in this regard are thecompounds where CO--R_(1*) is n-dodecanoyl.

With respect to the X substituent in the side chain in the 4-position ofthe 5-hydroxy-2(5H)-furanone molecule, the preferred compounds are thosewhere X is O, S, NH, SO, and SO₂.

With respect to the Y substituent in the side chain in the 4-position ofthe 5-hydroxy-2(5H)-furanone molecule, the preferred compounds used inthe method of the invention are those where Y is long chain alkyl,particularly where the alkyl group is straight chained and has more than10 carbons; the n-dodecyl group is especially preferred in this regard.Compounds are also preferred where Y is (CH₂)_(n) --O--(CH₂)_(m)--O--R₄, particularly where n is 1, m is 2, and R₄ is methyl. Furtherwith respect to the substituent group Y, compounds are preferred where Yis CO--R₃, CO--OR₃, CONHR₃, SO₂ R₃, SO₂ NHR₃ and where R₃ is long chainalkyl, particularly straight chained long chain alkyl, most preferablywhere R₃ is n-dodecyl. Alternatively, compounds are preferred in thelatter category where R₃ is phenyl substituted straight chain alkyl ofat least 4 carbons (or substituted phenyl substituted straight chainalkyl of at least 4 carbons); in certain particularly preferredembodiments of the invention Y is CO--R₃ with R₃ being5-(4-methoxyphenyl)-n-pentyl. Still further, compounds are preferredwithin the scope of the present invention where Y is PO(OH)₂, PO(OH)R₅,where R₅ is long chain alkyl, preferably long chain n-alkyl, mostpreferably n-dodecyl, or Y is PO(OR₅)₂, where R₅ is lower alkyl, mostpreferably ethyl, and still further where Y is PO(OH)O(CH₂)_(n) --N⁺(R_(5*))₃ particularly where n is 2 and where R_(5*) is methyl.

Examples of preferred compounds in accordance with Formula 3 are asfollows:

    __________________________________________________________________________    Compound 20:                                                                          X = O                                                                              R.sub.1 = H                                                                              Y = CH.sub.2 O(CH.sub.2).sub.2 OCH.sub.3 ;            Compound 21:                                                                          X = O                                                                              R.sub.1 = H                                                                              Y = PO(OH)(CH.sub.2).sub.11 CH3;                      Compound 22:                                                                          X = O                                                                              R.sub.1 = H                                                                              Y = CONH(CH.sub.2).sub.11 CH.sub.3 ;                  Compound 23:                                                                          X = O                                                                              R.sub.1 = H                                                                              Y = (CH.sub.2).sub.11 CH.sub.3 ;                      Compound 24:                                                                          X = NH                                                                             R.sub.1 = H                                                                              Y = CO(CH.sub.2).sub.11 CH.sub.3 ;                    Compound 25:                                                                          X = NH                                                                             R.sub.1 = H                                                                              Y = CONH(CH.sub.2).sub.11 CH.sub.3 ;                  Compound 26:                                                                          X = NH                                                                             R.sub.1 = H                                                                              Y = SO.sub.2 (CH.sub.2).sub.11 CH.sub.3 ;             Compound 27:                                                                          X = S                                                                              R.sub.1 = H                                                                              Y = (CH.sub.2).sub.11 CH.sub.3 ;                      Compound 28:                                                                          X = SO                                                                             R.sub.1 = H                                                                              Y = (CH.sub. 2).sub.11 CH.sub.3 ;                     Compound 29:                                                                          X = O                                                                              R.sub.1 = H                                                                              Y = PO(OCH.sub.2 CH.sub.3).sub.2 ;                    Compound 30:                                                                          X = O                                                                              R.sub.1 = CO(CH.sub.2).sub.10 CH.sub.3                                                   Y = PO(OCH.sub.2 CH.sub.3).sub.2 ;;                   Compound 31:                                                                          X = O                                                                              R.sub.1 = H                                                                              Y = POO.sup.- O(CH.sub.2).sub.2 N.sup.+ (CH.sub.3)                            .sub.3 ;                                              Compound 32:                                                                          X = NH                                                                             R.sub.1 = H                                                                              Y = COO(CH.sub.2).sub.11 CH.sub.3 ;                   Compound 33:                                                                          X = NH                                                                             R.sub.1 = H                                                                              Y = PO(OH)(CH.sub.2).sub.11 CH.sub.3 ;                Compound 34:                                                                          X = SO.sub.2                                                                       R.sub.1 = H                                                                              Y = (CH.sub.2).sub.11 CH.sub.3 ;                      Compound 35:                                                                          X = O                                                                              R.sub.1 = H                                                                              Y = CO(CH.sub.2).sub.5 -(4-methoxy)phenyl;            Compound 36:                                                                          X = NH                                                                             R.sub.1 = H                                                                              Y = SO.sub.2 NH(CH.sub.2).sub.11 CH.sub.3 ;           Compound 37:                                                                          X =  O                                                                             R.sub.1 = CO(CH.sub.2).sub.10 CH.sub.3                                                   Y = PO(OH).sub.2.                                     __________________________________________________________________________

The compounds corresponding to Formula 3, including the preferredcompounds identified in connection therewith can be prepared inaccordance with the disclosure of U.S. Pat. No. 5,037,811, thespecification of which is expressly incorporated herein by reference.

Example 3 ##STR26##

The compounds which are preferred in the method of treatment of thepresent invention and which are designated by Formula 4 above, have thefollowing preferred structural features.

The preferred compounds utilized in accordance with the presentinvention, with reference to Formula 4 and with respect to R substituentare those where R is alkyl, preferably long chain alkyl, and even morepreferably long chain n alkyl.

With respect to the substituent group X on the alpha carbon of the sidechain in the 3-position of the 2(5H)-furanone moiety, the preferredcompounds are those where X is O or NH.

With respect to the Y substituent on the hydroxyl or amino function inthe side chain in the 3-position of the 2(5H)-furanone moiety, compoundsare preferred where Y is H, acyl particularly acetyl. Also preferred arecarbamates (where Y is CONHR₃) particularly where Y is CONHC₆ H₅, andcarbonates (where Y is COOR₃) particularly where R₃ is lower alkyl,still more preferably ethyl. Compounds are also preferred where Y isPO(OR₂)₂ particularly where R₂ is lower alkyl, still more preferablyethyl. Other preferred compounds, with respect to the substituent Y, arethose where Y is SO₂ R₃ or (CH₂)_(n) --O--(CH₂)_(m) --O--R₃, morepreferably where R₃ is lower alkyl, still more preferably methyl.

The most preferred compounds corresponding to this example are thoselisted below with reference to Formula 26:

    ______________________________________                                        Compound 40: X = O     n = 7    Y = CH.sub.3 CO;                              Compound 41: X = O     n = 11   Y = H;                                        Compound 42: X = O     n = 11   Y = CH.sub.3 CO;                              Compound 43: X = O     n = 11   Y = CONHC.sub.6 H.sub.5 ;                     Compound 44: X = O     n = 11   Y = COOC.sub.2 H.sub.5 ;                      Compound 45: X = NH    n = 11   Y = COCH.sub.3 ;                              Compound 46: X = NH    n = 11   Y = SO.sub.2 CH.sub.3.                        ______________________________________                                         ##STR27##                                                                    Formula 26                                                                    (U.S. Pat. No. 5,043,457 400 23 PA, formula 9 of the patent)

The compounds corresponding to Formula 4, including the preferredcompounds identified in connection therewith and shown by Formula 26 canbe prepared in accordance with the disclosure of U.S. Pat. No.5,043,457, the specification of which is expressly incorporated hereinby reference.

Example 4 ##STR28##

The compounds which are preferred in the method of treatment of thepresent invention and which are designated by Formula 5 above, have thefollowing preferred structural features. R is preferably alkyl of 7 to20 carbons and R₁ is preferably OCOR₂ where R₂ is alkyl of 1 to 14carbons. Alternatively R is 2-(methoxy)ethoxymethoxymethyl and R₁ isOCO--(C₇ -C₁₄ alkyl).

The most preferred compounds of this example are:4-[1-dodecanoyloxy-2-(2-methoxyethoxy)methoxymethyl]-2(5H)-furanone(Compound 50), 4-(1-acetoxytridecyl)-2(5H)-furanone (Compound 51),4-[-((R)-(+)-α-methylbenzylcarbamyloxy)tridecyl]-2(5H)-furanone(Compound 52), and 4-(1-hydroxytridecyl)-2(5H)-furanone (Compound 53).

The compounds corresponding to Formula 5, including the preferredcompounds identified in connection therewith can be prepared inaccordance with the disclosure of U.S. Pat. No. 5,045,564, thespecification of which is expressly incorporated herein by reference.

Example 5 ##STR29##

Examples of compounds which are preferred in the method of treatment ofthe present invention and which are designated by Formula 6 above, areas follows: 4-(5-oxo-3-hexadecenyl)-5-hydroxy-2(5H)-furanone (Compound60), 4-(3-dodecanoyloxypropyl)-5-hydroxy-2(5H)-furanone (Compound 61),4-(2-carbomethoxytridecyl)-5-hydroxy-2(5H)-furanone (Compound 62), and4-(2-carbooctanoxyethyl)-5-hydroxy-2-(5H)-furanone (Compound 63).

The compounds corresponding to Formula 6, including the preferredcompounds identified in connection therewith can be prepared inaccordance with the disclosure of U.S. Pat. No. 5,059,611, thespecification of which is expressly incorporated herein by reference.

Example 6 ##STR30##

The compounds which are preferred in the method of treatment of thepresent invention and which are designated by Formula 7 above, have thefollowing preferred structural features. With respect to the 5-positionof the furanone moiety, those compounds are preferred where thesubstituent is hydroxy or acetoxy (R₁ is H or CH₃ CO).

With respect to the nitrogen on the beta carbon in the side chain (inthe 4-position) of the furanone moiety, the preferred compounds used inthe method of treatment of the invention are those where R₂ is hydrogen.

With respect to the alpha hydroxyl function in the side chain (in the4-position) of the furan moiety, preferred compounds are where: thehydroxyl is unsubstituted (X═H), is esterified with an acid having thestructure R₃ --COOH, (R₃ is defined as for Formula 7), the hydroxyl isconverted into a carbonate (X═CO--O--R₃) or carbamate (X═CO--NH--R₃).Particularly preferred in regard to this alpha hydroxyl function areacetate and propionate esters (X═COCH₃ or X═COCH₂ CH₃), esters of longchain fatty acids such as dodecanoic acid (X═CO(CH₂)₁₀ CH₃), esters ofalpha-omega dicarboxylic acids, such as glutaric acid, or esters of longchain dicarboxylic acids (e.g. X═CO(CH₂)₃ COOH or (X═CO(CH₂)₁₀ COOH),carbonates where X═CO--O--R₃ and R₃ is alkyl, especially ethyl,carbamates where X═CO--NH--R₃ and R₃ is phenyl or alkyl.

With respect to the amino function in the side chain (in the 4-position)of the furan moiety, (Formula 7) preferred compounds are: alkylsulfonamides (Y═SO₂ R₄) particularly where the alkyl group (R₄) ismethyl or alkyl of 6 to 20 carbons; carboxamides (Y═CO-- R₄) formed fromalkanoic acids, dialkylamino-substituted carboxamides derived from omegadialkylamino-substituted alkanoic acids (Y═CO--R₄ and R₄ is, forexample, (CH₃)₂ N(CH₂)₃), carboxamides derived from benzoic acid orsubstituted benzoic acid, including carboxamides derived from carboxysubstituted benzoic acids (e.g. Y═CO--R₄ and R₄ is C₆ H₃ (COOH)₂),carboxamides derived from alpha-omega dicarboxylic acids(Y═CO--(CH₂)_(n) COOH, for example n is 3 or 10); alkyl phosphonatesparticularly where Y is PO(OR₄)R₄ (R₄ is alkyl, particularly loweralkyl); alkyl carbamates (Y═CO--O--R₄) particularly where the alkylgroup R₄ has 6 to 20 carbons); and urea derivatives (Y═CO--NH--R₄ orY═CO--N--(R₄)₂) particularly in the former case where R₄ is alkyl of 6to 20 carbons, or in the latter case R₄ is ethyl. Also preferred areurea derivatives where Y is CO--N-methylpiperazinyl,methylsulfon-substituted N-piperazinyl, or N-morpholinyl group.

Examples of preferred compounds in accordance with Formula 7 are asfollows:

4-(2-undecanylamido-1-hydroxy)ethyl-5-hydroxy-2(5H)-furanone (Compound70), 4-(1-acetoxy-2-undecanylamido)ethyl-5-hydroxy-2(5H)-furanone(Compound 71),4-(2-undecanylamido-1-dodecanoyloxy)ethyl-5-hydroxy-2(5H)-furanone(Compound 72),4-[1-acetoxy-2-(dodecanesulfonylamido)ethyl]-5-hydroxy-2(5H)-furanone(Compound 73),4-[1-dodecanoyloxy-2-(3-carboxypropaneamido)]ethyl-5-hydroxy-2(5H)-furanone(Compound 74),4-[(1-hydroxy-2-(10-carboxydecaneamido)]ethyl-5-hydroxy-2(5H)-furanone(Compound 75),4-[(1-acetoxy-2-(10-carboxydecaneamido)]ethyl-5-hydroxy-2(5H)-furanone(Compound 76), 4-[1-dodecanoyloxy-2-(N'-methanesulfonylpiperazine)amido]ethyl-5-hydroxy-2(5H)-furanone (Compound 77),4-[1-dodecanoyloxy-2-(N',N'-diethyl)carboxyamido]ethyl-5-hydroxy-2(5H)-furanone(Compound 78).

The compounds corresponding to Formula 7, including the preferredcompounds identified in connection therewith can be prepared inaccordance with the disclosure of U.S. Pat. No. 5,081,147, thespecification of which is expressly incorporated herein by reference.

Example 7 ##STR31##

The compounds which are preferred in the method of treatment of thepresent invention and which are designated by Formula 8 and Formula 9above, have the following preferred structural features. With respect tothe 5-position of the furanone moiety, those compounds are preferredwhere the substituent is hydroxy or acetoxy (R₁ is H or CH₃ CO).

With respect to the R₃ substituent on the beta carbon in the side chain(in the 4-position) of the furanone moiety, the preferred compounds arethose where R₃ is hydrogen.

With respect to the R₂ substituent on the sulfonamide nitrogen, thepreferred compounds are those where R₂ is hydrogen, or where R₂ and Yjointly comprise a heterocycle which incorporates the sulfonamidenitrogen as a heteroatom. In addition to mono-substituted sulfonamides(R₂ =H) further preferred compounds in this regard are those where R₂, Yand the sulfonamide nitrogen jointly comprise a piperazine ring.

With respect to the Y substituent on the sulfonamide nitrogen, thepreferred compounds are those where Y is alkyl, more preferably straightchain alkyl, and still more preferably "long chain" alkyl, for exampleof 7 to 20 carbon atoms. Also preferred are compounds where Y isstraight chain alkyl substituted with a terminal OH, , dialkylamino,carboxy, or with a phosphate-oxy group (in Formula 8 and in Formula 9 Yis alkyl substituted with OH, N(R_(5*))₂ groups, or Y is alkylsubstituted with COR₅ group where R₅ is OH, or Y is alkyl substitutedwith O--PO(OR₅)₂ group where R₅ is alkyl or hydroxyl. Also preferred arecompounds where Y is substituted phenyl, more preferably carboxysubstituted phenyl.

Still with reference to Formula 8 and Formula 9, as applicable, and withrespect to the X substituent on the alpha hydroxyl function in the sidechain of the furanone molecule, the preferred compounds used in themethod of the invention are those where X is hydrogen, or an acyl group,preferably an acyl group derived from an alkanoic acid having a straightalkyl chain, or an acyl group derived from a straight chain alpha, omegadicarboxylic acid. Still more specifically in this regard, compounds aremore preferred where X is COCH₃, CO(CH₂)₁₀ CH₃, or CO(CH₂)₃ COOH.Compounds are also preferred where the alpha hydroxyl function isconverted into a carbamate, more preferably into a phenylcarbamate,derivative (X is CONHC₆ H₅. Examples of preferred compounds used in themethod of treatment of the invention are those listed just below withreference to Formula 27 and Formula 28, or by full chemical name:

Compound 80:4-[2-(N-dodecylsulfonamido)]-2-ethenyl-5-hydroxy-2(5H)-furanone;

Formula 27, Compound 81: R₆ =H, R₇ =CH₃ (CH₂)₁₁ ;

Formula 27, Compound 82: R₆ =COCH₃, R₇ =CH₃ (CH₂)₁₁ ;

Formula 27, Compound 83: R₆ =CO(CH₂)₃ COOH, R₇ =CH₃ (CH₂)₁₁ ;

Formula 27, Compound 84: R₆ =CO(CH₂)₁₀ CH₃, R₇ =(CH₂)₃ OH;

Formula 27, Compound 85: R₆ =CO(CH₂)₁₀ CH₃, R₇ =(CH₂)₂ COOH;

Formula 27, Compound 86: R₆ =CO(CH₂)₁₀ CH₃, R₇ =(CH₂)₃ OPO(OEt)₂ ;

Formula 27, Compound 87: R₆ =CO(CH₂)₁₀ CH₃, R₇ =(CH₂)₃ OPO(OH)₂ ;

Formula 27, Compound 88: R₆ =CO(CH₂)₁₀ CH₃, R₇ =(CH₂)₂ N(CH₃)₂ ;

Formula 27, Compound 89: R₆ =CO(CH₂)₁₀ CH₃, R₇ =para-carboxyphenyl (C₆H₄ COOH);

Formula 28, Compound 90: R₆ =H, R₈ =CH₃ ;

Formula 28, Compound 91: R₆ =CO(CH₂)₁₀ CH₃, R₈ =CH₃ ;

Formula 28, Compound 92: R₆ =CO(CH₂)₁₀ CH₃, R₈ =CH₃, salt with CH₃ I(quaternary amine);

Formula 28, Compound 93: R₆ =CONHC₆ H₅, R₈ =CH₃. ##STR32##

The compounds corresponding to Formula 8 and to Formula 9, including thepreferred compounds identified in connection therewith and shown inFormula 27 and Formula 28 can be prepared in accordance with thedisclosure of U.S. Pat. No. 5,081,261, the specification of which isexpressly incorporated herein by reference.

Example 8 ##STR33##

The compounds which are preferred in the method of treatment of thepresent invention and which are designated by Formula 10 above, have thefollowing preferred structural features. R is preferably C₁ -C₆carbamoyl, phenylcarbamoyl, C₁ -C₆ dialkyl phosphonate or PO(OH)₂. R₁ ispreferably chloro, acetamido, methoxycarbonylamino, sulfonamide,4-carboxybutanoyloxy, 4-carbomethoxybutanoyloxy, 2-methoxyethoxymethoxy,ethoxycarbonyloxy, 4-bromobutanoyloxy or 4-iodobutanoyloxy. R₂ ispreferably C₈ -C₂₀ alkyl.

Examples of preferred compounds in accordance with Formula 10 are asfollows:

4-(1-thioacetoxytridecyl)-5-hydroxy-2(5H)-furanone (Compound 100);4-[1-(glutarylamido)-tridecyl]-5-hydroxy-2(5H)-furanone (Compound 101);4-[1-(N-methylcarbamoyl)-N-methyl)carbamoyl]tridecyl-5-hydroxy-2(5H)furanone(Compound 102); 4-[(1-phenylcarbamoyl)tridecyl]-5-hydroxy-2(5H)-furanone(Compound 103);4-[1-ethoxycarbonyloxy)-tridecyl]-5-hydroxy-2(5H)-furanone (Compound104); 4-[1-(4-carboxybutanoyloxy)tridecyl]-5-hydroxy-2(5H)-furanone(Compound 105);4-[1-4-carbomethoxybutanoyloxy)tridecyl]-5-hydroxy-2(5H)-furanone(Compound 106);4-[1-(2-methoxyethoxy)methoxytridecyl]-5-hydroxy-2(5H)-furanone;4-[1-(methylsulfonamido)-tridecyl]-5-hydroxy-2(5H)-furanone (Compound107); 4-(1-(methoxycarbonylamino)tridecyl]-5-hydroxy-2(5H)-furanone(Compound 108);4-[1-(4-bromobutanoyloxy)tridecyl]-5-hydroxy-2(5H)-furanone (Compound109), and 4-[1-PO(OCH₃)CH₃ O-tridecyl]5-hydroxy-2(5H)-furanone (Compound110).

The compounds corresponding to Formula 10, including the preferredcompounds identified in connection therewith can be prepared inaccordance with the disclosure of U.S. Pat. No. 5,089,485, thespecification of which is expressly incorporated herein by reference.

Example 9 ##STR34##

The compounds which are preferred in the method of treatment of thepresent invention and which are designated by Formula 11 above, have thefollowing preferred structural features. With respect to the dotted linein Formula 11, it preferably represents a single bond. The R₁ group ispreferably hydrogen or C₁ -C₂₀ alkanoyl. The R₃ -Z group is preferablyin the 4-position of the furanone ring. The R₂ group is preferablyhydrogen or C₁ -C₂₀ alkanoyl. The R₃ group is preferably hydrogen, C₁-C₂₀ straight chain alkyl, phenyl(C₁ -C₂₀ straight chain alkyl),cyclohexyl(C₁ -C₂₀ straight chain alkyl), phenyl, cyclohexyl orbenzothienyl(C₁ -C₂₀ alkyl), 4-methyl-3-pentenyl,4-methyl-6-(2,6,6-trimethylcyclohex-1-enyl)hex-3-enyl,1-(2-ethenyl)-1,5,9-trimethyldeca-4,8-dienyl, Y--(CH₂)_(n) orB-(straight chain C₃ -C₁₄ alkynyl). Examples of preferred compounds usedin the method of treatment of the present invention and corresponding toFormula 11 are as follows: 4-(1-acetoxy-7-benzo(b)thien-2-ylheptyl]-5-hydroxy-2(5H)-furanone (Compound 120);4-(1-hydroxy-tridecyl)-5-hydroxy-2(5H)-furanone (Compound 121);4-(1-acetoxy-tridecyl)-5-hydroxy-2(5H)-furanone (Compound 122);4-(1-acetoxy-6-phenylhexyl)-5-hydroxy-2(5H)-furanone (Compound 123);4-(1-acetoxy-6-(2-naphtyl)hexyl)-5-hydroxy-2(5H)-furanone (Compound124); 4-(1-(α-methylbenzylcarbamoyl)tridecyl)-5-hydroxy-2(5H)-furanone(Compound 125), and4-[1-acetoxy-5-methyl-7-(2,6,6-trimethylcyclohex-1-enyl)-hept-4-e(Compound 126).

The compounds which are shown by Formula 11, including the preferredcompounds identified in connection therewith can be prepared inaccordance with the disclosure of application Ser. No. 07/699,819,assigned to the same assignee as the present application, which has beenallowed. The specification of this allowed application is expresslyincorporated herein by reference.

Example 10 ##STR35##

5-hydroxy-4-(1-keto)undecyl-2(5H)-furanone (Compound 130), is an exampleof a compound in accordance with Formula 12 which is preferred inaccordance with the method of treatment of the present invention. Thiscompound can be prepared in accordance with the disclosure ofapplication Ser. No. 07/699,819, assigned to the same assignee as thepresent application, which has been allowed. The specification of thisallowed application is expressly incorporated herein by reference.

Example 11 ##STR36##

The compounds which are preferred in the method of treatment of thepresent invention and which are designated by Formula 14 above, have thefollowing preferred structural features. R₂₀ is preferably C₁ -C₁₄alkanoyl. A is preferably CH₂ --O--C₈ -C₁₄ alkanoyl, CH₂--O-napthylpropyl, pyridylpropyl, or methoxyethoxymethoxymethyl. R₂₅ ispreferably hydrogen or C₁ -C₆ alkanoyl. Examples of such preferredcompounds are:4-[1-dodecanoyloxy-2-(2-methoxyethoxy)methoxyethyl]-5-hydroxy-2(5H)-furanone(Compound 140); 4-(1,2-didodecanoyloxyethyl)-5-hydroxy-2(5H)-furanone(Compound 141);4-[1-acetoxy-2-[3-(2-naphthyl)propoxy]ethyl]-5-hydroxy-2(5H) -furanone(Compound 142), and4-[1-hydroxy-2-[3-(2-naphthyl)propoxy]ethyl]-5-hydroxy-2(5H)-furanone(Compound 143).

The compounds which are shown by Formula 14, including the preferredcompounds identified in connection therewith can be prepared inaccordance with the disclosure of application Ser. No. 07/699,819,assigned to the same assignee as the present application, which has beenallowed. The specification of this allowed application is expresslyincorporated herein by reference.

Example 12 ##STR37##

The compounds which are preferred in the method of treatment of thepresent invention and which are designated by Formula 15 above, have thefollowing preferred structural features. The pyranyl ring is preferablyattached to the 4-position of the 2-furanone ring. The R₁ group ispreferably phenyl (C₁ -C₁₇ alkyl) or benzothienyl (C₁ -C₁₇ alkyl). R₂and Y are preferably hydrogen. Preferred compounds corresponding toFormula 15 are as follows:4-[3,6-dihydro-6-hydroxy-5-(3-phenylpropyl)-2H-pyran-2-yl]-5-hydroxy-2(5H)-furanone(Compound 150) and4-[5-(6-(benzo[b]thien-2-yl)-hexyl)-3,6-dihydro-6-hydroxy-2H-pyran-2-yl]-5-hydroxy-2(5H)-furanone(Compound 151).

The compounds which are shown by Formula 15, including the preferredcompounds identified in connection therewith can be prepared inaccordance with the disclosure of application Ser. No. 07/709,550,assigned to the same assignee as the present application, which has beenallowed. The specification of this allowed application is expresslyincorporated herein by reference.

Example 13 ##STR38##

The compounds which are preferred in the method of treatment of thepresent invention and which are designated by Formula 16 above, have thefollowing preferred structural features. The R₁ group is preferablyphenyl (C₁ -C₁₇) alkyl, the R₃ is preferably hydrogen or CH₃ CO, and theY group is preferably hydrogen. The following are examples of preferredcompounds corresponding to Formula 16:5-hydroxy-5-[5-hydroxy-2(5H)-furanon-4-yl]-2-(3-phenylpropyl)-penten-2-al(Compound 160);5-hydroxy-5-[5-hydroxy-2(5H)-furanon-3-yl]-2-(3-phenylpropyl)penten-2-al(Compound 161);5-acetoxy-5-[5-hydroxy-2(5H)-furanon-4-yl]-2-(3-phenylpropyl)-penten-2-al(Compound 162), and5-acetoxy-5-[5-hydroxy-2(5H)-furanon-3-yl]-2-(3-phenylpropyl)-penten-2-al(Compound 163).

The compounds which are shown by Formula 16, including the preferredcompounds identified in connection therewith can be prepared inaccordance with the disclosure of application Ser. No. 07/709,550,assigned to the same assignee as the present application, which has beenallowed. The specification of this allowed application is expresslyincorporated herein by reference.

Examples 14 and 15 ##STR39##

The compounds which are preferred in the method of treatment of thepresent invention and which are designated by Formula 17 above, have thefollowing preferred structural features. With respect to the R₁substituent in the 5 position of the 2-furanone molecule, the preferredcompounds are those where R₁ is hydrogen, long chain alkyl, orarylalkyl. Compounds are particularly preferred in this regard where theR₁ group is long chain alkyl which is straight chained, or where the R₁is arylalkyl containing a straight alkyl chain of 3 carbons.

With respect to the R₂ substituent in the 4 -position of the 2-furanonemolecule, compounds are preferred where R₂ is hydrogen, or alkyl group,particularly straight chain alkyl.

With respect to position 3 of the 2-furanones of the invention,compounds are preferred where R₃ is H, methyl or bromo. ##STR40##

The compounds which are preferred in the method of treatment of thepresent invention and which are covered by Formula 18 have the samepreferred R₁, R₂, and R₃ substituents as the preferred compounds ofFormula 17. With respect to the OX substituent in the 5-position of thefuranone moiety in Formula 18, those compounds are preferred where thesubstituent is hydroxy, methoxy or acetyloxy (X is H, or CH₃ O or CH₃CO).

Examples of preferred compounds corresponding to Formula 17 (Example 14)and to Formula 18 (Example 15) are listed below.

Formula 17, Compound 170: R₁ =CH₃ (CH₂)₈, R₂ =H, and R₃ =H;

Formula 18, Compound 171: R₁ =CH₃ (CH₂)₈, R₂ =H, R₃ =H and X=H;

Formula 17, Compound 172: R₁ =(CH₂)₃ --C₆ H₅, R₂ =CH₃, and R₃ =CH₃ ;

Formula 18, Compound 173: R₁ =H, R₂ =CH₃ (CH₂)₇, R₃ =Br and X=H, and

Formula 17, Compound 174: R₁ =H, R₂ =CH₃ (CH₂)₇ and R₃ =H.

The compounds of Examples 14 and 15 can be made in accordance with thesynthetic chemical pathways illustrated by the following specificexamples. The practicing synthetic organic chemist can readily modifythe chemical pathways provided by these reactions and specific examplesto prepare any and all compounds represented by Formula 17 and Formula18.

Ethyl 4-hydroxy-6-phenylhex-1-ynoate

n-Butyl lithium (a 1.6M solution in hexane; 6.7 ml, 10.7 mmol) was addeddropwise to a solution of ethyl propiolate (1.04 g, 10.6 mmol) intetrahydrofuran (10 ml) at -78° under argon. After 10 minutes, asolution of hydrocinnamaldehyde (1.42 g, 10.6 mmol) in tetrahydrofuran(5 ml) was added. Stirring was continued at -78° C. for 2 hours andacetic acid (1 ml) was added. On warming up to 0°, the reaction mixturewas poured into water. Extraction (ethyl ether) and evaporation of thedried (magnesium sulphate) extracts afforded an oil, which was flashchromatographed with silica using 30% ethyl ether/petroleum ether.Fractions with R_(f) of about 0.28 on evaporation afforded the titleester as a light yellow oil.

¹ NMR (CDCl₃) 1.34 (m, 3H), 2.10 (m, 2H), 2.40 (br, 1H), 2.83 (t, 2H,J=8.3 Hz), 4.25 (q, 2H, J=7.3 Hz), 4.50 (t, 1H, J=7.0 Hz) and 7.29 (m,5H).

LRMS m/e (% abundance) 233 (M⁺ +1, 2), 232 (M⁺, 7), 186 (24), 185 (42),170 (51), 169 (30), 158 (24), 142 (37), 141 (100) and 105 (84).

5-(2-Phenylethyl)-2(5H)-furanone

A solution of ethyl 4-hydroxy-6-phenylhex-1-ynoate (585 mg, 2.5 mmol) inether (12 ml) was hydrogenated over Lindlar catalyst (50 mg) at roomtemperature for 3 hours. The mixture was filtered through celite and thefiltrate was refluxed with 2M hydrochloric acid (1 ml) for 21/2hours. Oncooling, the mixture was dried (magnesium sulphate) and evaporated todryness to give an oil, which was purified by preparative thin layerchromatography (tlc, 20×20 cm, 2000u silica plate; developed with 30%ethyl ether/petroleum ether). The title furanone was obtained ascolorless prisms (recrystallized from ether): mp 66°-7°.

¹ H NMR (CDCl₃) 1.98-2.16 (m, 2H), 2.86 (m, 2H), 5.08 (m, 1H), 6.16 (dd,1H, J=6.0 Hz, 1.6 Hz), 7.36 (m, 5H) and 7.45 (dd, 1H, J=6.0 Hz, 1.6 Hz).

¹³ C NMR (CDCl₃) 31.3, 34.9, 82.3, 121.5, 126.3, 128.5, 128.6, 140.2,156.1 and 172.9.

HRMS exact mass calculated for C₁₂ H₁₂ O₂ (M⁺) 188.0837, found 188.0841.

4-Hydroxy-6-phenylhex-2-ynoic acid

A solution of potassium hydroxide (377 mg, 6.7 mmol) in 95% ethanol (10ml) was added to a solution of ethyl 4-hydroxy-6-phenylhex-1-ynoate(1.04 g, 4.5 mmol) in the same solvent (10 ml) at 0°, and the reactionmixture was stirred at room temperature for 15 hours. After most of thesolvent was removed, the residue was dissolved in water (ca. 15 ml) andextracted with dichloromethane (discarded). After the extraction theaqueous phase was acidified to pH 1 with dilute hydrochloric acid andextracted thoroughly with ethyl acetate. Evaporation of the dried(magnesium sulphate) extracts gave the title acid as a pale yellow oil(which crystallizes slowly on standing), which was used directly in thenext step.

¹ H NMR (CDCl₃) 2.16 (m, 2H), 2.85 (m, 2H), 4.52 (dd, 1H, J=11.3 Hz, 6.6Hz), 5.10 (br, 2H) and 7.31 (m, 5H).

LRMS m/e (% abundance) 204 (M⁺, 6), 142 (42), 141 (75), 134 (21), 133(11), 131, (10), 118 (34), 117 (32), 115 (21) and 105 (100).

4-Keto-6-phenylhex-2-ynoic acid

A solution of Jones Reagent (a 2.67M solution in sulphuric acid; 2.07ml, 5.5 mmol) was added dropwise to a solution of4-hydroxy-6-phenylhex-2-ynoic acid (750 mg, 3.7 mmol) in acetone (12 ml)at 0° and the reaction mixture was maintained at 0° for 70 minutes. Themixture was quenched with ethanol (2 ml) and extracted with ethyl ether.Evaporation of the dried (magnesium sulphate) extracts gave the titleacid as a yellow oil which was used directly in the next step.

¹ NMR (CDCl₃) 3.02 (s, 4H), 7.30 (m, 5H) and 8.80 (br, 1H, exchangedwith D₂ O).

5-Hydroxy-5-(2-phenylethyl)-2-furanone

A solution of 4-keto-6-phenylhex-2-ynoic acid (228 mg, 1.1 mmol) inethyl ether (8 ml) was hydrogenated over Lindlar catalyst (20 mg) at 0°for 80 minutes. The mixture was filtered through celite and thefiltrate, after evaporation to dryness, was purified by preparative tlc(20×20 cm, 1000u silica plate; developed with 60% ethyl ether/hexane).The title furanone was obtained as a colorless oil.

¹ H NMR (CDCl₃) 2.31 (dd, 2H, J=10.8 Hz, 5.5 Hz), 2.78 (dd, 2H, J=10.8Hz, 5.5 Hz), 4.80 (br, 1H), 6.11 (d, 1H, J=5.8 Hz), 7.20 (m, 5H) and7.28 (d, 1H, J= 5.8 Hz).

¹³ C NMR (CDCl₃) 29.7, 39.1, 107.8, 123.1, 126.4, 128.3, 128.7, 140.3,154.3 and 171.0.

HRMS exact mass calculated for C₁₂ H₁₂ O₃ (M⁺) 204.0786, found 204.0792.

Ethyl 4-hydroxytridec-2-ynoate

Methylmagnesium bromide (a 3M solution in tetrahydrofuran; 7.8 ml, 23.4mmol) was added dropwise to a solution of ethyl propiolate (2.25 g, 22.9mmol) in tetrahydrofuran (10 ml) at -78° under argon. After 10 minutes,a solution of decyl aldehyde (3.58 g, 22.9 mmol) in tetrahydrofuran (2ml) was added. Stirring was continued for 1 hour while the cooling bathwas warmed to room temperature. The mixture was quenched with saturatedammonium chloride solution and extracted with ethyl ether. Evaporationof the dried (magnesium sulphate) extracts gave an oil, which was flashchromatographed on silica using 30% ethyl ether/petroleum ether.Fractions with R_(f) of about 0.31 gave, after evaporation, the titleester as a deep, yellow oil.

¹ H NMR (CDCl₃) 0.88 (t, 3H, J=6.4 Hz), 1.27 (br s, 14H), 1.75 (m, 2H)and 4.25 (q, 2H, J=6.4 Hz).

LRMS m/e (% abundance) 255 (M⁺ +1, 5), 254 (M⁺, 5), 237 (6), 209 (8),181 (12), 179 (11), 163 (13), 152 (12), 151 (13), 137 (16), 130 (19),128 (100), 100 (66) and 71 (35).

5-Nonyl-2(5H)-furanone (Compound 170)

A solution of ethyl 4-hydroxytridec-2-ynoate (230.6 ml, 1.02 mmol) inether (10 ml) was hydrogenated over Lindlar catalyst (20 mg) at 0° for 1hour. The mixture was filtered through celite and after evaporation thefiltrate gave a residue, which was flash chromatographed on silica using60% ethyl ether/petroleum ether. Fractions with R_(f) of about 0.18 gaveafter evaporation a colorless oil (157 mg, 59%) identified by ¹ H NMR asethyl (E)-4-hydroxytridec-2-enoate: ¹ H NMR (CDCl₃) 0.92 (t, 3H, J=6.7Hz), 1.31 (br s, 14H), 1.65 (m, 2H), 4.97 (q, 1H, J=6.2 Hz), 5.91 (d,1H, J=12.5 Hz) and 6.41 (dd, 1H, J=12.5 Hz, 7.3 Hz). The oil oncrystallization from petroleum ether, in the presence of a drop ofacetic acid, lactonized to give the title furanone as a colorless oil.

¹ H NMR (CDCl₃) 0.92 (t, 3H, J=6.7 Hz), 1.30 (br s, 12H), 1.45 (m, 2H),1.75 (m, 2H), 5.08 (m, 1H), 6.14 (dd, 1H, J=5.9 Hz, 2.6 Hz) and 7.48(dd, 1H, J=5.3 Hz, 1.4 Hz).

¹³ C NMR (CDCl₃) 14.1, 22.6, 25.0, 29.2, 29.3, 29.4, 31.8, 33.2, 83.4,121.5, 156.3 and 173.1.

HRMS m/e: exact mass calculated for C₁₃ H₂₂ O₂ (M⁺) 210.1620, found210.1624.

4-Hydroxytridec-2-ynoic acid

A solution of potassium hydroxide (885 mg, 15.8 mmol) in 95% ethanol (35ml) was added to ethyl 4-hydroxytridec-2-ynoate (2.68 g, 10.5 mmol) inthe same solvent (5 ml) at 0°. After stirring at room temperature for 9hours, most of the solvent was removed and water (20 ml) was added. Themixture was extracted thoroughly with dichloromethane (discarded),acidified to pH 1 with dilute hydrochloric acid and extracted with ethylacetate. Evaporation of the dried (magnesium sulphate) ethyl acetateextracts gave an off-white solid, which on recrystallization frompetroleum ether (at -78°) gave the title acid as colorless prisms: mp65°-6°.

¹ H NMR (CDCl₃) 0.93 (t, 3H, J=5.7 Hz), 1.31 (br s, 12H), 1.50 (br, 1H),1.81 (m, 2H), 4.56 (dt, 1H, J=5.0 Hz, 1.9 Hz) and 5.00 (br, 1H).

LRMS m/e (% abundance) 226 (M⁺, 5), 137 (13), 124 (12), 121 (18), 107(26), 100 (94), 97 (33), 95 (27), 93 (43) 85 (48), 83 (63), 79 (55) and71 (75).

4-Ketotridec-2-ynoic-acid

Jones reagent (a 2.67M solution in sulphuric acid; 1.32 ml, 3.5 mmol)was added dropwise to a solution of 4-hydroxytridec-2-ynoic acid (531.8mg, 2.4 mmol) in acetone (10 ml) at 0° and the reaction mixture wasmaintained at 0° for 70 minutes. The mixture was quenched with ethanol(1 ml) and dried with magnesium sulphate. On evaporation, the title acidwas obtained as a colorless oil.

¹ H NMR (CDCl₃) 0.87 (t, 3H, J=6.6 Hz), 1.25 (br s, 12H), 1.67 (m, 2H),2.64 (t, 2H, J=7.2 Hz) and 4.90 (br, 1H).

LRMS m/e (% abundance) 224 (M⁺, 5), 223 (12), 197 (36), 155 (37), 149(14), 37 (21), 123 (15), 111 (14), 109 (12) and 97 (34).

5-Hydroxy-5-nonyl-2-furanone (Compound 171)

A solution of 4-ketotridec-2-ynoic acid (220 mg, 0.98 mmol) in ether (10ml) was hydrogenated over Lindlar catalyst (10 mg) at 0° for 80 minutes.The mixture was filtered through celite and after evaporation to drynessthe filtrate gave an oil, which was purified by preparative tlc (20×20cm, 1000u silica plate; developed with 60% ethyl ether/petroleum ether).The title furanone was obtained as colorless prisms (recrystallized frompetroleum ether): mp 54°-5°.

¹ H NMR (CDCl₃) 0.88 (t, 3H, J=7.5 Hz), 1.26 (br s, 12H), 1.40 (m, 2H),1.98 (m, 2H), 6.12 (d, 1H, J= 6.4 Hz) and 7.16 (d, 1H, J=6.4 Hz).

¹³ C NMR (CDCl₃) 14.1, 22.6, 23.4, 29.3, 29.4, 31.8, 37.5, 108.5, 123.0,154.5 and 170.8.

HRMS m/e: exact mass calculated for C₁₃ H₂₂ O₃ (M⁺) 226.1569, found226.1568.

5-Hydroxy-5-methyl-4-octyl-2-furanone

A mixture of 2-undecanone (10 g, 58.7 mmol), glyoxylic acid monohydrate(5.15 g, 56 mmol) and 85% phosphoric acid (10 ml) was warmed at 80° for18 hours. On cooling to room temperature, the mixture was diluted withethyl ether/dichloromethane (50 ml each) and washed thoroughly withbrine. Evaporation of the dried (magnesium sulphate) organic phase gavea yellow oil which on crystallization from ethyl ether/petroleum ethergave 4-ketotridec-2-enoic acid as colorless prisms.

¹ H NMR (CDCl₃) 0.96 (t, 3H, J=7.4 Hz), 1.34 (br s, 12H), 1.72 (p, 2H,J=7.1 Hz), 2.73 (t, 2H, J=7.1 Hz), 6.74 (d, 1H, J=15.7 Hz) and 7.22 (d,1H, J=15.7 Hz).

The mother liquor from the above recrystallization was concentrated downand was flash chromatographed on silica using 40% ethylacetate/petroleum ether. Fractions with R_(f) of about 0.1 gave, afterevaporation, the title furanone as a pale yellow oil.

¹ H NMR (CDCl₃) 0.92 (t, 3H, J=7.4 Hz), 1.30 (br s, 12H), 2.45 (s, 3H),2.79 (t, 2H, J=7.5 Hz) and 6.56 (s, 1H).

¹³ C NMR (CDCl₃) 14.1, 22.7, 26.7, 27.0, 29.2, 29.3, 29.8, 31.9, 124.5,158.0, 171.3 and 200.0.

HRMS m/e: exact mass calculated for C₁₃ H₂₂ O₃ (M⁺) 226.1569, found226.1559.

5-Methyl-4-octyl-2(5H)-furanone

Sodium borohydride (214 mg, 5.7 mmol) was added to a solution of5-hydroxy-5-methyl-4-octyl-2-furanone (640 mg, 2.8 mmol) intetrahydrofuran (15 ml). After stirring at room temperature for 80minutes, most of the solvent was removed and water (10 ml) was added.Extraction (dichloromethane) and evaporation of the dried (magnesiumsulphate) extracts gave a residue, which was flash chromatographed onsilica using 60% ethyl ether/petroleum ether. Fractions with R_(f) ofabout 0.23 were evaporated to yield the title furanone as a colorlessoil, which crystallized slowly on storage at -70°.

¹ H NMR (CDCl₃) 0.85 (t, 3H, J=5.4 Hz), 1.26 (br s, 10H), 1.33 (d, 3H,J=6.9 Hz), 1.47 (m, 2H), 2.26 (m, 1H), 2.83 (m, 1H), 4.33 (q, 1H, J=6.2Hz) and 5.99 (s, 1H).

¹³ C NMR (CDCl₃) 14.1, 22.4, 22.6, 29.2, 29.3, 29.5, 29.8, 31.9, 71.1,113.0, 169.2 and 171.8.

HRMS m/e exact mass calculated for C₁₃ H₂₂ O₂ (M⁺) 210.1620, found210.1617.

4-Ethyl-5-hydroxy-5-methyl-2-furanone

A mixture of 2-pentanone (17.1 g, 198 mmol), glyoxylic acid monohydrate(8.05 g, 88 mmol) and about 85% phosphoric acid (12 ml) was warmed atca. 80° for 19 hours. On cooling to room temperature the mixture wasdiluted with ethyl ether/dichloromethane (100 ml, 1:1) and washedthoroughly with brine. Evaporation of the dried (magnesium sulphate)organic phase gave a yellow viscous oil, which on crystallization fromethyl ether/petroleum ether gave 4-keto-hept-2-enoic acid as colorlessprisms: mp 100°-2°.

¹ H NMR (CDCl₃) 1.01 (t, 3H, J=7.9 Hz), 1.73 (p, 2H, J=7.1. Hz), 2.70(t, 2H, J=7.3 Hz), 6.73 (1H, d, J=15.8 Hz) and 7.19 (d, 1H, J=15.8 Hz).

HRMS m/e: exact mass calculated for C₇ H₁₀ O₃ (M⁺) 142.0630, found142.0622.

The mother liquor from the above crystallization was evaporated todryness and extracted thoroughly with petroleum ether. The combinedextracts were concentrated and cooled to -20° to give the title furanoneas colorless prisms: mp 37°-8°.

¹ H NMR (CDCl₃) 1.09 (t, 3H, J=7.8 Hz), 2.46 (s, 3H), 2.83 (q, 2H),J=7.8 Hz) and 6.57 (s, 1H).

¹³ C NMR (CDCl₃) 13.6, 20.4, 26.6, 124.6, 158.7, 171.2 and 199.9.

HRMS m/e: exact mass calculated for C₇ H₁₀ O₃ (M⁺) 142.0630, found142.0622.

4-Ethyl-5-methyl-2(5H)-furanone

Sodium borohydride (646 mg, 17 mmol) was added to a solution of4-ethyl-5-hydroxy-5-methyl-2-furanone (1.21 g, 8.5 mmol) intetrahydrofuran (10 ml) at room temperature. After 1/2 hour, most of thesolvent was removed and water (10 ml) was added. Extraction (ethylacetate) and evaporation of the dried (magnesium sulphate) extracts gavean oil, which was flash chromatographed on silica using 60% ethylether/petroleum ether. Fractions with R_(f) of about 0.23 gave afterevaporation, a pale yellow oil, which slowly crystallized on storage at-20°. Recrystallization from ethyl ether/petroleum ether afforded thetitle furanone as colorless prisms: mp 86°-7°.

¹ H NMR (CDCl₃) 1.16 (t, 3H, J=7.2 Hz), 1.39 (d, 3H, J=5.4 Hz), 2.36 (m,1H), 2.84 (m, 1H), 4.41 (q, 2H, J=7.2 Hz) and 6.04 (s, 1H).

¹³ C NMR (CDCl₃) 13.8, 22.3, 22.8, 71.0, 112.9, 170.3 and 171.7.

HRMS m/e: exact mass calculated for C₇ H₁₀ O₂ (M⁺) 126.0681, found126.0683.

3,4-Dimethyl-5-hydroxy-5-(1-octynyl)-2-furanone

n-Butyl lithium (a 1.6M solution in hexane; 6.78 ml, 10.9 mmol) wasadded dropwise to a solution of 1-octyne (1.13 g, 10 mmol) intetrahydrofuran (7 ml) at -78° under argon. After 20 minutes, thesolution was cannulated dropwise, under argon, to a solution of2,3-dimethylmaleic anhydride (1.30 g, 10.3, mmol) in tetrahydrofuran (15ml) cooled at -78°. Stirring was continued for 2 hours while the coolingbath attained room temperature. The mixture was quenched with dilutehydrochloric acid, diluted with water (10 ml) and extracted with ethylacetate. Evaporation of the dried (magnesium sulphate) extracts gave anoil, which was flash chromatographed on silica using 30% ethylether/petroleum ether. Fractions with R_(f) of about 0.18 on evaporationafforded a light yellow viscous oil, which crystallized out slowly onstorage at -20°. Recrystallization from petroleum ether gave the titlefuranone as colorless prisms: mp 55°-6° C.

¹ H NMR (CDCl₃) 0.85 (t, 3H, J=7.4 Hz), 1.24 (m, 6H), 1.49 (p, 2H, J=7.9Hz), 1.79 (s, 3H), 2.00 (s, 3H), 2.21 (t, 2H, J=7.2 Hz) and 3.93 (br,1H).

¹³ C NMR (CDCl₃) 8.4, 10.5, 13.9, 18.5, 22.4, 27.9, 28.4, 31.1, 74.5,88.2, 98.0, 124.3, 156.9 and 172.1.

HRMS m/e: exact mass calculated for C₁₄ H₂₀ O₃ (M⁺) 237.1491, found237.1498.

3,4-Dimethyl-5-hydroxy-5-(3-phenylpropyl)-2-furanone

A mixture of 3-phenyl-1-bromopropane (521 mg, 2.6 mmol) and magnesiumturnings (66 mg, 2.8 mmol) in tetrahydrofuran (5 ml) was refluxed underargon for 90 minutes. After the reaction mixture had been cooled to-78°, a solution of 2,3-dimethylmaleic anhydride (330 mg, 2.6 mmol) intetrahydrofuran (5 ml) was added dropwise. Stirring was continuedovernight (ca. 17 hours) while the cooling bath attained roomtemperature. The mixture was quenched with a saturated solution ofammonium chloride and extracted with ethyl acetate. Evaporation of thedried (magnesium sulphate) extracts gave an oil, which was flashchromatographed on silica using 40% ethyl acetate/petroleum ether.Fractions with R_(f) of about 0.32 on evaporation afforded the titlefuranone as a pale yellow oil, which on storage at -20° crystallized ascolorless prisms: mp 62°-3° C.

¹ H NMR (CDCl₃) 1.48 (m, 1H), 1.70 (m, 1H), 1.79 (s, 3H), 1.89 (s, 3H),2.05 (m, 2H), 2.65 (m, 2H) and 7.25 (m, 5H).

¹³ C NMR (CDCl₃) 8.3, 10.6, 24.7, 35.4, 107.2, 125.1, 125.9, 128.4,141.5, 158.1 and 172.6.

HRMS m/e: exact mass calculated for C₁₅ H₁₈ O₃ (M⁺) 246.1256, found246.1270.

3,4-Dimethyl-5-(3-phenylpropyl)-2(5H)-furanone (Compound 172)

Potassium borohydride (503 mg, 9.3 mmol) was added to a solution of3,4-dimethyl-5-hydroxy-5-(3-phenylpropyl)-2-furanone (382 mg, 1.6 mmol)in tetrahydrofuran (8 ml) and methanol (6 ml) at room temperature. After7 hours, most of the solvent was removed and water (10 ml) was added.Extraction (ethyl acetate) and evaporation of the dried (magnesiumsulphate) extracts gave an oil, which was purified by preparative tlc(20×20 cm, 2000u silica plate; developed with 30% ethyl ether/petroleumether). The title furanone was obtained as colorless prisms(recrystallized from ethyl ether/petroleum ether): mp 69°-70°.

¹ H NMR (CDCl₃) 1.50 (m, 1H), 1.77 (p, 2H, J=6.8 Hz), 1.82 (s, 3H), 1.92(s, 3H), 1.95 (m, 1H), 2.67 (m, 2H), 4.74 (m, 1H) and 7.25 (m, 5H).

¹³ C NMR (CDCl₃) 8.4, 11.9, 26.0, 31.5, 35.4, 82.9, 123.6, 125.9, 128.4,141.5 and 158.9.

HRMS m/e: exact mass calculated for C₁₅ H₁₈ O₂ (M⁺) 230.1307, found230.1311.

4-Octyl-5-hydroxy-2(5H)-furanone

A mixture of glyoxylic acid monohydrate (1.19 g, 16.1 mmol), morpholinehydrochloride (1.81 g, 14.6 mmol), water (0.73 ml) and 1-decanal (2.89ml, 15.4 mmol) in dioxane (6 ml) was stirred at room temperature for 1hour, followed by reflux for 25 hours. After cooling, most of thesolvent was removed by evaporation and the residue was extracted withethyl ether. Evaporation of the dried (magnesium sulfate) extracts gavean oil, which was flash chromatographed with 30% ethyl acetate/hexane togive the title furanone.

¹ H NMR (CDCl₃): 0.89 (t, 3H, J=6.6 Hz), 1.25 (br s, 10H), 1.60 (m, 2H),2.40 (m, 2H), 4.70 (br, 1H), 5.84 (s, 1H) and 6.00 (s, 1H).

4-Octyl-5-methoxy-2(5H)-furanone

A mixture of 4-octyl-5-hydroxy-2(5H)-furanone (244 mg, 1.16 mmol) and4-toluenesulfonic acid (33 mg, 0.17 mmol) and methanol (5.8 ml) wasstirred at room temperature for 2 days. The mixture was diluted withethyl ether and washed thoroughly with 5% sodium bicarbonate solution.Evaporation of the dried (magnesium sulfate) organic phase gave an oil,which was flash chromatographed on silica using 10% ethyl acetate/hexaneto give the title furanone.

¹ H NMR (CDCl₃): 0.89 (t, 3H, J=7.5 Hz), 1.28 (br s, 10H), 1.60 (m, 2H),2.35 (m, 2H), 3.56 (s, 3H), 5.64 (s, 1H) and 5.86 (s 1H).

3-Bromo-4-octyl-5-methoxy-2(5H)-furanone

A solution of bromine (28 microliter) in carbontetrachloride (0.2 ml)was added to a solution of 4-octyl-5-methoxy-2(5H)-furanone (100 mg,0.45 mmol) in carbon tetrachloride (0.5 ml) at 0°. The mixture wasstirred at room temperature until all the starting material disappeared(as monitored by tlc). After cooling to 0°, pyridine (86 microliter,1.17 mmol) was added. The mixture was quenched with water and the layerswere separated. Evaporation of the dried (magnesium sulfate) organicphase gave an oil, which was purified by flash chromatography using 5%ethyl acetate/hexane to give the title furanone.

¹ H NMR (CDCl₃): 0.89 (t, 3H, J=6.8 Hz), 1.28 (br s, 15H), 1.60 (m, 2H),2.50 (m, 2H), 3.58 (s, 3H) and 5.69 (s, 1H).

3-Bromo-4-octyl-5-hydroxy-2(5H)-furanone (Compound 173)

A mixture of 3-bromo-4-octyl-5-methoxy-2(5H)-furanone (106 mg, 0.35mmol) and concentrated hydrochloric acid (0.21 ml) was refluxed untilall the starting material disappeared as shown by tlc. After cooling,the mixture was diluted with ethyl ether and was neutralized by washingthoroughly with saturated potassium bicarbonate solution.. Evaporationof the dried (magnesium sulfate) organic phase gave an oil, which wasflash chromatographed on silica using 10% ethyl acetate/hexane to givethe title furanone.

IR (CHCl₃): 3389, 1755 and 1651.

¹ H NMR (CDCl₃): 0.87 (t, 3H, J=7.2 Hz), 1.27 (br s, 10H), 1.60 (m, 2H),2.49 (t, 2H, J=8.5 Hz), 4.50 (br, 1H), and 6.05 (s, 1H).

¹³ C NMR (CDCl₃): 14.2, 22.7, 26.5, 27.8, 29.2, 29.6, 31.8, 98.8, 112.1and 163.9.

HRMS exact mass calculated for C₁₂ H₂₀ BrO₃ (M+H)⁺ 291.0596, found291.0590.

Examples 16 and 17 ##STR41##

The compounds which are preferred in the method of treatment of thepresent invention and which are designated by Formula 19a and 19b above,have the following preferred structural features. With respect to the R₁substituent those compounds are preferred where R₁ is alkyl of 1 to 6carbons, more preferably methyl or butyl, and where R₁ is phenyl.

With respect to Y₁ in Formula 19 compounds are preferred where Y₁ is H,acyl, more preferably acetyl, and where Y₁ represents a phenylcarbamoyl(C₆ H₅ --NH--CO--) group. Y₁ also preferably represents a lauroyl (CH₃--(CH₂)₁₀ --CO) group, particularly when Y₂ is H.

With respect to Y₂ of Formula 19 compounds are preferred in accordancewith the method of the present invention where Y₂ is long chain normalalkyl, preferably normal alkyl of 8 to 25 carbon atoms; particularlypreferred are compounds where Y₂ represents a normal dodecyl group.

The Y₃ group of Formula 19 is preferably H, or acetyl.

With respect to n, compounds are preferred where n is 1; also preferredare the compounds where n is 2 and where Y₂ is H.

Examples of preferred compounds shown by Formula 19 are listed belowwith continuing reference to reference to Formula 19a, where for thelisted specific examples Y₃ =H.

Compound 180: n=1, R₁ =5-methyl, Y₁ =CH₃ CO; Y₂ =(CH₂)₁₁ --CH₃

Compound 181: n=1, R₁ =3-methyl, Y₁ =CH₃ CO; Y₂ =(CH₂)₁₁ --CH₃

Compound 182: n=1, R₁ =3-methyl, Y₁ =C₆ H₅ --NHCO; Y₂ =(CH₂)₁₁ --CH₃

Compound 183: n=1, R₁ =5-methyl, Y₁ =C₆ H₅ --NHCO; Y₂ =(CH₂)₁₁ --CH₃

Compound 184: n=1, R₁ =5-butyl, Y₁ =C₆ H₅ --NHCO; Y₂ =(CH₂)₁₁ --CH₃

Compound 185: n=2, R₁ =3-phenyl, R₁ =methyl, Y₁ =CO--(CH₂)₁₀ --CH₃ ; Y₂=H

Compound 186: n=1, R₁ =5-methyl, Y₁ =CO--(CH₂)₁₀ --CH₃ ; Y₂ =H

Compound 187: n=1, R₁ =3-phenyl, Y₁ =C₆ H₅ --NHCO; Y₂ =(CH₂)₁₁ --CH₁

Compound 188: n=1, R₁ =3-phenyl, Y₁ =CH₃ CO; Y₂ =(CH₂)₁₁ --CH₃ ##STR42##

An example of a compound utilized in the method of treatment of thepresent invention and covered by Formula 20a is4-dodecoyloxymethyl-5-hydroxy-5-methyl-3-phenyl-2-furanone (Compound189).

The compounds of Examples 16 and 17 can be made in accordance with thesynthetic chemical pathways illustrated by the following specificexamples. The practicing synthetic organic chemist can readily modifythe chemical pathways provided by these specific reactions and examplesto prepare any and all compounds represented by Formula 19a and b andFormula 20a and b. Generally speaking, the compounds of Formula 19b and20b can be prepared by sodium borohydride reduction of a compound ofFormula 19a or 20a where the 5 position bears an OH group (Y₃ =H).

2-Trimethylsilyl-4-furaldehyde

n-Butyl lithium (a 2.5M solution in hexane; 28.8 ml, 72 mmol) was addedto a solution of morpholine (6.28 ml, 72 mmol) in tetrahydrofuran (700ml) at -78° under argon. After 20 minutes, 3-furaldehyde (7.0 g, 72mmol) was added. After another 20 minutes, sec-butyl lithium (a 1.3Msolution in cyclohexane; 55.4 ml, 72 mmol) was added dropwise andstirring continued at -78° for 7 hours before trimethylsilyl chloride(27 ml, 216 mmol) was added. Stirring was continued overnight (14 hours)while the cooling bath was allowed to attain room temperature. Thesolution was poured into ice cold 10% (v/v) hydrochloric acid (200 ml)and after stirring at 0° for 10 minutes, the layers were separated. Theaqueous phase was extracted with diethyl ether. All the organic phaseswere combined, dried (magnesium sulfate) and evaporated to dryness togive a light brown oil, which was purified by flash chromatography onsilica using 2% ethyl ether/hexane. Fractions with R_(f) of about 0.30(silica, 10% ethyl ether/hexane) on evaporation gave the title aldehydeas a light yellow oil, b.p. 48°-50°/0.25 torr.

¹ H NMR (CDCl₃) 0.29 (s, 9H), 6.98 (s, 1H), 8.25 (s, 1H) and 9.95 (s,1H).

¹³ C NMR (CDCl₃) -2.0, 116.2, 128.9, 155.3, 164.1 and 184.5.

HRMS exact mass calculated for C₈ H₁₂ O₂ Si(M⁺) 168.0607, found168.0588. See also U.S. Pat. No. 4,935,530, the specification of whichis incorporated herein by reference.

2-Triethylsilyl-4-furaldehyde

n-Butyl lithium (a 2.5M solution in hexane; 30.6 ml, 76.5 mmol) wasadded to a solution of morpholine (6.66 ml, 76.5 mmol) intetrahydrofuran (500 ml) at -78° under argon. After 15 minutes,3-furaldehyde (6.3 ml, 72.8 mmol) was added. After another 20 minutes,sec-butyl lithium (a 1.3M solution in cyclohexane; 59.0 ml, 76.5 mmol)was added dropwise and stirring continued at -78° for about 2 hoursbefore triethylsilylchloride (13.4 ml, 80.1 mmol) was added. Stirringwas continued overnight (14 hours) while the cooling bath was allowed toattain room temperature. The solution was poured into ice cold 10% (v/v)hydrochloric acid (100 ml) and after stirring at 0° for 10 minutes, thelayers were separated. The aqueous phase was extracted with diethylether. All the organic phases were combined, dried (magnesium sulfate)and evaporated down to give an oil, which was distilled under highvacuum to give the 5-triethylsilyl-3-furaldehyde as a pale yellow oil,boiling point 85°-90°/0.4 torr.

IR (neat) 1680cm⁻¹

¹ H NMR (CDCl₃) 0.79 (q, 6H, J=7.3 Hz), 0.90 (t, 9H, J=7.3 Hz), 7.0 (s,1H), 8.26 (s, 1H) and 9.95 (s, 1H).

¹³ C NMR (CDCL3) 2.9, 7.1, 117.2, 128.8, 155.6, 162.3 and 184.6.

HRMS m/e exact mass calculated for C₁₁ H₁₈ O₂ Si(M⁺) 210.1076, found210.1071. See also U.S. Pat. No. 4,935,530, the specification of whichis incorporated herein by reference.

2-(tert-Butyldimethylsilyl)-4-furaldehyde

n-Butyl lithium (a 2.5M solution) in hexane; 8.3 ml, 20.8 mmol) wasadded to a solution of morpholine (1.81 ml, 20 mmol) in tetrahydrofuran(100 ml) at -78° C. under argon. After 20 minutes 3-furaldehyde (1.8 ml,20.8 mmol) was added. After another 15 minutes, sec-butyl lithium (a1.3M solution in cyclohexane; 16.8 ml, 21.9 mmol) was added dropwise andstirring continued at -78° C. for 1 hour before a solution oft-butyldimethylsilyl chloride (9.4 g, 62.4 mmol) in tetrahydrofuran (10ml) was added. Stirring was continued overnight (16 hours) while thecooling bath was allowed to attain room temperature. The solution waspoured into ice cold 10% (v/v) hydrochloric acid (40 ml) and afterstirring at 0° for 10 minutes, the layers were separated. The aqueousphase was extracted with diethyl ether. All the organic phases werecombined, dried (magnesium sulfate) and evaporated to dryness to give abrown oil, which was distilled under high vacuum to give the titlealdehyde, boiling point 80°-5°/0.5 torr., m.p. 37°-8°.

¹ H NMR (CDCl₃) 0.23 (s, 6H), 0.90 (s, 9H), 6.99 (s, 1H), 8.25 (s, 1H)and 9.94 (s, 1H).

¹³ C NMR (CDCl₃) 16.6, 26.1, 117.3, 128.8, 155.5, 162.7 and 184.5.

HRMS exact mass calculated for C₁₁ H₁₈ O₂ Si (M⁺) 210.1076, found210.1075.

5-Methyl-2-trimethylsilyl-4-furaldehyde

n-Butyl lithium (a 1.6M solution in hexane; 2.04 ml, 3.28 mmol) wasadded dropwise to a solution of N,N'N'-trimethylethylenediamine (0.46ml, 3.56 mmol) in tetrahydrofuran (7 ml) at -78 degrees under argon.After 15 minutes, a solution of 2-trimethylsilyl-4-furaldehyde (0.5 g,2.98 mmol) in tetrahydrofuran (2 ml) was added, followed by n-butyllithium (3.72 ml, 5.94 mmol) after 15 minutes. Iodomethane (1.12 ml,17.9 mmol) was then added and the mixture was allowed to warm to roomtemperature gradually over 1/2 hour. The mixture was quenched with brineand extracted with ethyl ether. Evaporation of the dried (magnesiumsulphate) extracts gave an oil, which was purified by flashchromatography using 10% ethyl ether/hexane. Fractions with R_(f) ofabout 0.22 on evaporation afforded the title methylfuran as a lightyellow oil.

'H NMR (CDCl₃) 0.29 (s, 9H), 2.63 (s, 3H), 6.91 (s, 1H) and 9.95 (s,1H).

LRMS m/e (% abundance) 183 (M⁺ +1, 35), 167 (28), 149 (20), 83 (40), 73(100) and 43 (31).

5-Methyl-4-(1-acetoxytridecyl)-2-trimethylsilylfuran

A mixture of 1-bromododecane (261 mg, 0.11 mmol) and magnesium turnings(27 mg, 0.11 mmol) in tetrahydrofuran (7 ml) was refluxed under argonfor 1 hour. After cooling to room temperature, a solution of5-methyl-2-trimethylsilyl-4-furaldehyde (158.6 mg, 0.87 mmol) intetrahydrofuran (1 ml) was added, followed by acetic anhydride (0.25 ml,2.6 mmol) after 1 hour. Stirring was continued at room temperatureovernight and the mixture was quenched with water. Extraction (ethylether) and evaporation of the dried (magnesium sulphate) extracts gavean oil, which was purified by preparative TLC (20×20 cm, 1000 micronsilica plate; developed with 5% ethyl ether/hexane). The title ester wasobtained as a light yellow oil.

'H NMR (CDCl₃) 0.26 (s, 9H), 0.91 (t, 3H, J=6.9 Hz), 1.27 (s, 20H),1.60-1.90 (m, 2H), 2.05 (s, 3H), 2.35 (s, 3H), 5.69 (t, 1H, J=7.5 Hz)and 6.55 (s, 1H).

LRMS m/e (% abundance) 394 (M⁺, 8), 352 (23), 334 (36), 183 (47), 167(20), 117 (28), 73 (100) and 43 (41).

4-(1-Acetoxytridecyl)-5-hydroxy-5-methyl-2-furanone (Compound 180)

A mixture of 5-methyl-4-(1-acetoxytridecyl)-2-trimethylsilylfuran (237mg, 0.60 mmol) and Rose Bengal (5 mg) in tetrahydrofuran (10 ml) wasexposed to singlet oxygen at -78 degrees C. for 2 hours. The residue,after solvent removal, was purified by preparative TLC (20×20 cm, 1000micron silica plate; developed with 60% ethyl ether/hexane). The titlefuranone was obtained as a light yellow oil. This compound is a mixtureof epimers which isomerizes upon standing.

'H NMR (CDCl₃) 0.92 (t, 3H, J=6.9 Hz), 1.30 (brs, 20H), 1.70 (brs, 3H),1.80 (m, 2H), 2.15 (2s, 3H), 5.25 (brm, 1H), 5.45 (t, 0.7H, J=7.5 Hz),5.96 (s, 0.7H), 6.03 (s, 0.3H) and 6.11 (brm, 0.3H).

¹³ C NMR (CDCl₃) 13.7, 20.5, 22.3, 23.3, 24.1, 24.9, 28.8, 29.0, 29.1,29.2, 29.3, 31.6, 33.2, 33.3, 69.0, 69.3, 106.5, 117.0, 118.1, 169.6,169.7, 169.8, 170.0, 170.1, 170.7, 171.9 and 172.0.

HRMS exact mass calculated for C₂₀ H₃₈ NO₅ (M+NH₄)⁺ 372.2749, found 372.2754

3-(O-tert-Butyldimethylsilylmethoxy)furan

3-Furylmethanol (15.5 ml, 0.18 mol), followed by1,8-diazabicyclo[5.4.0]undec-7-ene (29.7 ml, 0.19 mol) was added to asolution of tert-butyldimethylsilyl chloride (29.9 g, 0.19 m) indichloromethane (140 ml) at 0 degrees C. under argon. After stirring atroom temperature overnight, the reaction was quenched with ice coldhydrochloric acid. Extraction with dichloromethane and evaporation ofthe dried (magnesium sulfate) extracts gave an oil which was purified byflash chromatography on silica using hexane to give the desired silylether.

'H NMR (CDCl₃): 0.05 (s, 6H), 0.89 (s, 9H), 4.58 (s, 2H), 6.35 (1H) and7.33 (m, 2H).

3-(2-tert-Butyldimethylsilyl)furylmethanol

n-BuLi (a 1.5M solution in hexane; 38.9 ml, 58 mmol) was added to asolution of 3-(O-tert-butyldimethylsilylmethoxy)furan (11.2 g, 52.7mmol) and hexamethylphosphoramide(10.1 ml, 58 mmol) in tetrahydrofuran(200 ml) at -78 degrees C. under argon. After 1 hour stirring at -20degrees C., the reaction was quenched with an aqueous solution ofsaturated ammonium chloride. Extraction (ethyl acetate) and evaporationof the dried (magnesium sulfate) extracts gave an oil, which waspurified by flash chromatography on silica using 20% ethylacetate/hexaneto give the desired furylmethanol.

'H NMR (CDCl₃): 0.29 (s, 6H), 0.90 (s, 9H), 1.45 (brt, 1H), 4.59 (d, 2H,J=3.4 Hz), 6.49 (d, 1H, J=1.7 Hz) and 7.60 (d, 1H, J=1.7 Hz).

2-(tert-Butyldimethylsilyl)-3-hydroxymethyl-4-furaldehyde

n-BuLi (a 1.6M solution in hexane; 2.7 ml, 4.28 mmol) was added dropwiseto a solution of 3-(2-tert-butyldimethylsilyl)-furylmethanol (430 mg,2.0 mmol) in dimethoxyethane (5 ml) at -78 degrees C. under argon. Afterstirring at 0 degrees C. for 15 minutes, lithium chloride (860 mg, 20.4mmol), followed by N,N-dimethylformamide (0.35 ml, 4.48 mmol) was added.Stirring continued at 0 degrees C. for 16 hours and the mixture wasquenched with ammonium chloride. Extraction with ethyl acetate andevaporation of the dried (magnesium sulfate) extracts gave a solid,which was recrystallized from hexane to give the titled aldehyde.

IR (CHCl₃) 3470, 1680, 1660, 1570 and 1510.

'H NMR (CDCl₃) 0.28 (s, 6H), 0.87 (s, 9H), 4.08 (t, 1H, J=7.3 Hz), 4.58(d, 2H, J=7.3 Hz), 8.27 (s, 1H) and 9.90 (s, 1H).

¹³ CNMR (CDCl₃) 5.9, 17.1, 26.1, 55.4, 128.3, 133.9, 158.2, 158.3 and186.6.

LRMS m/e (% abundance) 258 [(M+NH₄)⁺,1], 240 (56), 223 (53), 184 (26),183 (10) and 167 (41).

4-[2-(tert-Butyldimethylsilyl)-3-methyl]furylmethanol

a) 3-(2-tert-Butyldimethylsilyl-4-carbonyl)furylmethyl methanesulfonate

A solution of 2-(tert-butyldimethylsilyl)-3-hydroxymethyl-4-furaldehyde(4.98 g, 20.7 mmol), diisopropylethylamine (7.95 ml, 45.6 mmol) intetrahydrofuran (70 ml) was added dropwise to a solution ofmethanesulfonyl chloride (6.42 ml, 82.9 mmol) in tetrahydrofuran (70 ml)at -20 degrees C. under argon. After stirring at -20 degrees C. for 90minutes, the mixture was diluted with ethyl ether and washedsuccessively with 10% hydrochloric acid, water and brine. Evaporation ofthe dried (magnesium sulfate) organic phase gave an oil, which waspurified by flash chromatography on silica using 20% ethylacetate/hexaneto give the titled mesylate.

'HNMR (CDCl₃) 0.36 (s, 6H), 0.93 (s, 9H), 3.16 (s, 3H), 5.33 (s, 2H),7.27 (s, 1H), 8.26 (s, 1H) and 10.02 (s, 1H).

b) 4-[2-(tert-Butyldimethylsilyl)-3-methyl]furylmethanol

Lithium aluminum hydride (a 1.0M solution in THF; 62.2 ml, 62.2 mmol)was added dropwise to a solution of the mesylate from above in THF (10ml) at -20 degrees C. under argon. After 20 minutes, TLC showed that thereaction has been completed. The mixture was quenched carefully withdil-hydrochloric acid. Extraction with diethyl ether and evaporation ofthe dried (magnesium sulfate) extracts gave an oil, which was purifiedby flash chromatography on silica using 20% ethylacetate/hexane to givethe titled alcohol.

IR (CHCl₃) 3450 and 1600

'HNMR (CDCl₃) 0.27 (s, 6H), 0.91 (s, 9H), 2.12 (s, 3H), 4.53 (s, 2H) and7.56 (s, 1H).

¹³ CNMR (CDCl₃) -6.1, 9.0, 17.5, 26.2, 55.4, 125.5, 130.8, 144.6 and155.1

LRMS m/e (% abundance) 226 (M⁺, 32), 209 (45), 170 (18), 169 (91), 142(13), 141 (100), 101 (10) 97 (41), 75 (93) and 73 (22).

2-(tert-Butyldimethylsilyl)-3-methyl-4-furaldehyde

A solution of 4-[2-(tert-butyldimethylsilyl)-3-methyl]furyl-methanol(380 mg, 1.68 mmol) in dichloromethane (5 ml) was added to a suspensionof barium permanganate (6.45 g, 25.2 mmol) in dichloromethane (40 ml) at0 degrees C. under argon. After stirring at room temperature for 15hours, the mixture was filtered through celite. After concentration byevaporation, the filtrate was purified by flash chromatography on silicausing 5% ethyl ether/hexane to give the titled aldehyde.

IR (CHCl₃) 2820, 2740 and 1680

'HNMR (CDCl₃) 0.2 (s, 6H), 0.82 (s, 9H), 2.23 (s, 3H), 8.09 (s, 1H) and9.91 (s, 1H).

¹³ CNMR (CDCl₃) -6.3, 9.8, 17.3, 25.9, 128.1, 129.9, 156.8, 157.6 and185.7.

LRMS m/e (% abundance) 224 (11), 168 (16), 167 (100), 83 (12) and 73(11).

4-(1-Acetoxytridecyl)-2-(tert-butyldimethylsilyl)-3-methylfuran

2-(tert-Butyldimethylsilyl)-3-methyl-4-furaldehyde (95 mg, 0.42 mmol)was added to a solution of dodecylmagnesium bromide (a 1.0M solution inTHF; 0.51 ml, 0.51 mmol) in THF (1 ml) at 0 degrees C. under argon. Whenall the aldehyde has reacted, acetic anhydride (80 microliter, 0.85mmol) was added. After stirring at room temperature for 16 hours, themixture was quenched with dilute hydrochloric acid. Extraction withdiethyl ether and evaporation of the dried (magnesium sulfate) extractsgave an oil, which was purified by flash chromatography on silica using5% ethyl ether/hexane to give the titled acetate.

IR (CHCl₃) 1730 and 1710.

'HNMR (CDCl₃) 0.26 (s, 6H), 0.88 (t, 3H, J=6.9 Hz), 1.25 (brs, 20H),1.80 (m, 2H), 2.03 (s, 3H), 2.07 (s, 3H), 5.78 (t, 1H, J=7.0 Hz) and7.52 (s, 1H)

¹³ CNMR (CDCl₃) -6.1, 9.5, 13.8, 17.5, 21.0, 22.5, 25.4, 26.2, 29.1,29.2, 29.3, 29.4, 31.7, 34.6, 68.4, 125.4, 130.2, 144.4, 154.7 and 170.7

LRMS m/e (% abundance) 436 (M⁺, 4), 320 (3), 211 (14), 118 (10), 117(100), 75 (22) and 73 (18).

4-(1-Acetoxytridecyl)-3-methyl-5-hydroxy-2(5H)-furanone (Compound 181)

A mixture of 4-(1-acetoxytridecyl)-2-(tert-butyldimethylsilyl3-methylfuran (132 mg, 0.3 mmol), water (a few drops) and Rose Bengal (5mg) in acetone (30 ml) was exposed to singlet oxygen at 0 degrees C. for6 hours. The residue, on evaporation, was purified by flashchromatography on silica using 20% ethylacetate/hexane to give thetitled furanone.

IR(CHCl)₃ 3400, 1780, 1750 and 1730.

¹ HNMR (CHCl₃) 0.82 (t, 3H, J=6.9 Hz), 1.20 (brs, 20H), 1.75 (m, 2H),1.85 (s, 3H), 2.03 (s, 3H), 2.06 (s, 3H), 5.35 (m, 2H), 5.88 (brs, 1H)and 6.08 (brs, 1H).

¹³ C NMR (CDCl₃) 9.2, 14.2, 20.8, 22.8, 25.6, 29.4, 29.5, 29.6, 29.7,29.8, 32.1, 32.8, 70.1, 70.7, 97.7, 128.5, 128.9, 156.5, 156.6, 171.7,172.1, 172.7 and 173.1.

LRMS m/e (% abundance) 355 (M⁺, 16), 296 (11), 295 (59), 294 (100), 277(19), 267 (45), 126 (34), 125 (41), 112 (18), 95 (23), 81 (22) and 69(27).

2-(tert-butyldimethylsilyl)-3-methyl-4-(1-phenylcarbamoyloxy)tridecylfuranand2-(tert-butyldimethylsilyl)-3-methyl-4-[1-N-phenyl-N-phenylcarbamoyl)carbamoyloxy]tridecylfuran

Dodecylmagnesium bromide (a 1.0M solution in THF; 0.89 ml, 0.89 mmol)was added to a solution of2-tert-butyldimethylsilyl-3-methyl-4-furaldehyde (Compound 26, 200 mg,0.89 mmol) in THF (5 ml) at 0 degrees C. under argon. After stirring atroom temperature for 1 hour, the mixture was recooled to 0 degrees C.and phenylisocyanate (97 microliter, 0.89 mmol) was added. Stirring wascontinued for 5 minutes and the reaction mixture was quenched withammonium chloride. Extraction with diethyl ether and evaporation of thedried (magnesium sulfate) extracts gave an oil. The crude product waspurified by flash chromatography (SiO₂ ; 5% ethylether/hexane) to givethe desired mono- and bis-phenylcarbonate.2-(tert-Butyldimethylsilyl)-3-methyl-4-(1-phenylcarbamoyloxy)tridecylfuran:R_(f) (5% diethyl ether/hexane) 0.34; IR (CHCl₃) 3430, 1725, 1680, 1595and 1515; 'HNMR (CDCl₃) 0.24 (s, 6H), 0.88 (t+s, 12H), 1.23 (m, 20 H),1.90 (m, 2H), 2.09 (s, 3H), 5.77 (t, 1H, J=7.0 Hz), 6.65 (s, 1H), 7.02(t, 1H, J=7.3 Hz), 7.25 (m, 2H), 7.35 (m, 2H) and 7.54 (s, 1H); ¹³ CNMR(CDCl₃) -6.1, 9.6, 13.8, 17.5, 22.4, 25.4, 26.2, 29.1, 29.2, 29.3, 29.4,31.7, 34.8, 69.5, 118.7, 123.5, 125.4, 129.2, 130.2, 138.2, 144.4, 153.4and 154.9.

2-(tert-Butyldimethylsilyl)-3-methyl4-[1-(N-phenyl-N-phenylcarbamoyl)carbomoyloxy]tridecylfuran: R_(f) (5%diethylether/hexane) 0.23; 'H NMR (CDCl₃) 0.24 (s, 6H), 0.87 (s+t, 12H),1.24 (m, 20H), 1.56 (m, 2H), 1.79 (s, 3H), 5.75 (t, 1H, J=6, 2Hz), 7.07(t, 1H, J=8.0 Hz), 7.20 (m, 2H), 7.30 (m, 3H), 7.42 (m, 3H), 7.54 (m,2H) and 10.9 (s, 1H); ¹³ CNMR (CDCl₃) -6.2, -6.1, 9.3, 13.6, 17.5, 22.4,24.9, 26.1, 28.8, 29.1, 29.2, 29.3, 29.4, 31.7, 34.4, 72.8, 120.0,124.0, 124.1, 128.4, 128.9, 129.0, 129.5, 137.4, 138.0, 144.3 , 151.8,155.3 and 155.6.

5-Hydroxy-3-methyl-4-(1-phenylcarbamoyloxy)tridecyl)-2(5H) furanone(Compound 182)

A mixture of2-(tert-butyldimethylsilyl)-3-methyl-4-(1-phenylcarbamoyloxy)tridecylfuran(226 mg, 0.44 mmol), water (a few drops) and polymer bound Rose Bengal(0.077 g) in acetone (80 ml) was exposed to singlet oxygen at 0 degreesC. for 5 hours. The residue, on evaporation, was purified by flashchromatography (SiO₂, 20% ethylacetate/hexane) to give the titledfuranone. IR (CHCl₃) 3400-3200, 1768, 1725, 1605 and 1520; 'HNMR (CDCl₃)0.88 (t, 3H, J=6.9 Hz), 1.26 (m, 20H), 1.80 (m, 1H), 1.91 (s, 3H), 1.95(m, 1H), 5.48 (brt, 1H), 5.52 (m, 1H), 5.95 (br, 1H), 6.04 (brs, 1H),6.19 (brs, 1H), 7.00-7.40 (m, 6H); ¹³ C NMR (CDCl₃) 8.7, 13.8, 22.4,25.2, 28.9, 29.1, 29.2, 29.3, 29.4, 29.5, 31.7, 32.4, 32.5, 69.9, 70.6,97.2, 97.4, 118.8, 119.0, 119.4, 123.9, 124.1, 128.1, 128.9, 129.2,137.3, 137.6, 153.2, 153.4, 153.6, 156.0, 156.8, 172.5 and 172.7.

5-Methyl-2-triethylsilyl-4-furaldehyde

n-Butyl lithium (a 1.6M solution in THF; 19.0 ml, 30.4 mmol) was addedto a solution of morpholine (2.67 ml, 30.4 mmol) in THF (20 ml) at -78degrees C. under argon. After 20 minutes, 3-furaldehyde (1.8 ml, 28.9mmol) was added, followed by s-butyl-lithium (a 1.3M solution incyclohexane; 23.4 ml, 30.4 mmol) after another 20 minutes. Stirring wascontinued for 2 hours and chlorotriethylsilane (5.1 ml, 30.4 mmol) wasadded. After 2 hours at -78 degrees C., s Buli (23.4 ml, 30.4 mmol) wasadded, followed by iodomethane (5.4 ml, 86.9 mmol) after another 2hours. The mixture was stirred at room temperature for 15 hours andquenched with ice cold dilute hydrochloric acid. Extraction withdiethylether and evaporation of the dried (magnesium sulfate) extractsgave an oil, which was purified by flash chromatography on silica using10% diethyl ether/hexane to give the titled aldehyde.

IR (CHCl₃) 1690

'HNMR (CDCl₃) 0.75 (q, 6H, J=8.0 Hz), 0.98 (t, 9H, J=8.0 Hz), 2.60 (s,3H), 6.90 (s, 1H) and 9.90 (s, 1H).

¹³ CNMR (CDCl₃) 2.6, 6.7, 12.5, 118.8, 122.8, 158.5, 166.2 and 185.1;HRMS exact mass calculated for C₁₂ H₂₀ O₂ S_(i) 224.1232 found 224.1226

4-(1-Acetoxytridecyl)-5-methyl-2-triethylsilylfuran

5-Methyl-2-triethylsilyl-4-furaldehyde (145 mg, 0.65 mmol) was added toa solution of dodecylmagnesium bromide (a 1.0M solution in THF; 0.76 ml,0.74 mmol) in THF at 0 degrees C. under argon. When all the aldehyde hasconsumed, acetic anhydride (0.16 ml, 1.71 mmol) was added. Stirring wascontinued at room temperature for 15 hours and the mixture was quenchedwith water. Extraction with diethyl ether and evaporation of the dried(magnesium sulfate) extracts gave an oil, which was purified by flashchromatography on silica using 5% diethyl ether/hexane to give thetitled acetate.

IR (CHCl₃) 1730

'HNMR (CDCl₃) 0.75 (q, 6H, J=8.0 Hz), 0.88 (t, 3H, J=7.0 Hz), 0.95 (t,9H, J=8.0 Hz), 1.25 (brs, 20H), 1.75 (m, 1H), 1.95 (m, 1H), 2.01 (s,3H), 2.31 (s, 3H), 5.69 (t, 1H, J=7.2 Hz) and 6.55 (s, 1H).

¹³ CNMR (CDCl₃) -2.9, 7.0, 11.9, 13.8, 21.0, 22.5, 25.3, 25.7, 29.0,29.2, 29.3, 29.4, 31.7, 34.8, 68.8, 118.8, 120.3, 154.1, 156.1 and170.7. LRMS m/e (% abundance) 436 (M⁺, 9), 377 (22), 376 (33), 347 (43),239 (29), 145 (100), 115 (34), 103 (30) and 87 (30); HRMS Exact MassCalculated For C₂₆ H₄₈ O₃ Si (M⁺) 43 6.3373, found 436.3374.

4-(1-Acetoxytridecyl)-5-hydroxy-5-methyl-2-furanone (Compound 180)

A mixture of 4-(1-acetoxytridecyl)-5-methyl-2-triethylsilylfuran (231mg, 0.53 mmol), water (a few drops) and Rose Bengal (6.3 mg) in acetone(100 ml) was exposed to singlet oxygen at 0 degrees C. for 3 hours. Theresidue, after evaporation, was purified by flash chromatography onsilica using 10% ethylacetate/hexane to give the titled furanone. Thiscompound is a mixture of epimers which isomerizes upon standing.

IR (CHCl₃) 3600-3200, 1770 and 1740.

For further physical data of Compound 180 see the description ofpreparing the same compound as above.

5-Methyl-2-triethylsilyl-4-(1-phenylcarbamoyloxy)tridecylfuran

A solution of 5-methyl-2-triethylsilyl-4-furaldehyde (219 mg, 0.98 mmol)in THF (5 ml) was added to a solution of dodecylmagnesium bromide (a1.0M solution in THF; 1.08 ml; 1.08 mmol) in THF at 0 degrees C. underargon. When all the aldehyde was consumed, phenylisocyanate (0.12 ml,1.08 mmol) was added. After stirring at room temperature for 16 hours,the mixture was quenched with dilute hydrochloric acid. Extraction withdiethyl/ether and evaporation of the dried (magnesium sulfate) extractsgave an oil, which was purified by flash chromatography on silica using5% diethyl/ether/hexane to give the titled furan.

IR (CHCl₃) 3440, 1730 and 1520.

'HNMR (CDCl₃) 0.72 (q, 6H, J=6.6 Hz), 0.88 (t, 3H, J=6.6 Hz), 0.98 (t,9H, J=6.6 (Hz), 1.25 (brs, 20H), 1.75 (m, 1H), 1.95 (m, 1H), 2.36 (s,3H), 5.70 (t, 1H, J=7.3 Hz), 6.57 (s, 1H), 6.62 (br, 1H), 7.02 (m, 1H),7.29 (m, 2H) and 7.37 (m, 2H).

¹³ CNMR (CDCl₃) 2.9, 7.1 11.9, 13.8, 22.5, 25.3, 29.1, 29.2, 29.3, 29.4,31.7, 35.0, 69.9, 118.7, 118.8, 120.2, 123.3, 129.1, 138.3, 144.8,153.5, 154.3 and 156.3.

5-Methyl-5-hydroxy-4-(1-phenylcarbamoyloxy)tridecyl-2-furanone (Compound183)

A mixture of 5-methyl-2-triethylsilyl-4-(1-phenylcarbamoyloxy)tridecylfuran (80 mg, 0.13 mmol) water (a few drops) and Rose Bengal(ca, 3 mg) in acetone (60 ml) was exposed to singlet oxygen at 0 degreesC. for 4 hours. The residue, after evaporation, was purified by flashchromatography on silica using 20% ethylacetate/hexane to give thetitled furanone.

IR (CHCL3) 3440, 3400-3240, 1765, 1730, 1600 and 1525.

'HNMR (CDCl₃) 0.88 (t, 3H, J=6.9 Hz), 1.26 (brs, 2H), 1.67 (brm, 2H),1.79 (brs, 3H), 5.18 (brm, 1H), 5.50 (brm, 1H), 5.85 (br, 1H), 6.03 (br,1H), 7.12 (m, 2H) and 7.40 (m, 3H).

¹³ CNMR (CDCl₃) 13.8, 22.4, 22.8, 24.2, 24.3, 24.8, 25.1, 28.9, 29.1,29.2, 29.3, 29.4, 31.7, 3.33, 34.0, 69.6, 70.2, 70.3, 98.2, 106.5,118.1, 119.2, 124.1, 124.3, 124.5, 129.3, 136.9, 153.9, 169.9 and 170.4.

LRMS m/e (% abundance) 431 (M⁺, 4), 277 (7), 153 (6), 137 (12), 126(12), 119 (25), 109 (11), 94 (13), 93 (100) and 55 (30).

5-Butyl-2-triethylsilyl-4-furaldehyde

Using the same procedure as for 5-methyl-2-trimethylsilyl-4-furaldehydebut substituting 2-trimethylsilyl-4-furaldehyde and methyl iodide with2-triethylsilyl-4-furaldehyde and 1-iodobutane, respectively, gives5-butyl-2-triethylsilyl-4-furaldehyde. IR (neat) 1690 cm-1; 'HNMR(CDCl₃) 0.73 (q, 6H, J=8.4 Hz), 0.95 (m, 12H), 1.36 (p, 2H, J=7.5 Hz),1.69 (p, 2H, J=7.5 Hz), 2.94 (t, 2H, J=7.5 Hz), 6.89 (s, 1H) and 9.91(s, 1H) ¹³ CNMR (CDCl₃): 3.03, 7.17, 13.6, 22.2, 26.8, 30.4, 118.6,122.5 158.4, 170.2 and 184.8. LRMS m/e (% abundance) 266 (M⁺, 20) 238(20) 237 (100), 87 (10) and 75 (20); HRMS exact mass calculated for C₁₅H₂₆ O₂ S_(i) 266.1702, found 266.1690.

5-Butyl-5-hydroxy-4-(1-phenylcarbamoyloxy)tridecyl-2-furanone (Compound184)

a) 5-Butyl-4-(1-phenylcarbamoyloxy)tridecyl-2-triethylsilylfuran

Dodecyl magnesium bromide (a 1.0M solution in THF; 0.25 ml, 0.25 mmol)was added to a solution of 5-butyl-2-triethylsilyl-4-furaldehyde (59 mg,0.22 mmol) in THF (1 ml) at 0 degrees C. under argon. When all thealdehyde has reacted, phenylisocyanate (27 microliter, 0.25 mmol) wasadded and stirring was continued at -40 degrees C. for 14 hours. Withoutpurification the crude product was used in the next step.

'HNMR (CDCl₃)

b) 5-Butyl-5-hydroxy-4-(1-phenylcarbamoyloxy)tridecyl-2-furanone(Compound 184)

Water (a few drops) and Rose Bengal (ca. 3 mg) were added to the abovereaction mixture. The mixture was exposed to singlet oxygen for 3 hoursat 0 degrees C. The residue, after evaporation, was purified bypreparative TLC (SiO₂) developed with 40% diethylether/hexane to givethe titled furanone. IR (CHCl₃) 3600-3240, 3440, 1770, 1760, 1730, 1605,1550 and 1530. 'HNMR (CDCl₃) 0.88 (m, 6H), 1.30 (brm, 22H), 1.50 (m,2H), 1.75 (m, 2H), 2.00 (m, 2H), 5.10 (brm, 1H), 5.70 (br, 1H), 6.04(brs, 1H), 6.95 (brs, 1H), 7.15 (brm, 1H), 7.30 (m, 3H) and 7.50 (m, 2H)

¹³ C NMR (CDCl₃) 13.6, 13.8, 22.1, 2.22, 22.4, 24.3, 24.6, 25.1, 28.6,28.9, 29.0, 29.1, 29.3, 29.4, 31.7, 32.9, 33.5, 36.3, 69.7, 108.3,118.9, 119.2, 119.4, 120.2, 124.5, 128.6, 129.0, 129.2, 129.3, 129.4,136.8, 169.2, 169.7 and 169.9. LRMS m/e (% abundance) 491[(M+NH₄)⁺, 67],474[(M+H)⁺, 86], 473 (M⁺, 23), 456 (33), 372 (30), 354 (30), 337 (66),319 (38), 272 (48), 213 (80), 120 (27) 119 (45), 94 (58) and 93 (100).

2 -tert-Butyldimethylsilyl-3,5-dimethyl-4-furaldehyde

Treatment of 2-tert-butyldimethylsilyl-4-hydroxymethyl-3-methylfuranwith n-butyl lithium and iodomethane gives2-tert-butyldimethylsilyl-3,5-dimethyl-4-hydroxymethylfuran. Oxydationof this furan with barium permanganate gives the titled furaldehyde.

2-Triethylsilyl-5-phenyl-4-furaldehyde.

Treatment of 2-triethylsilyl-4-furaldehyde with lithioN,N,N'-trimethylethylenediamine, followed by phenyltrifluoromethanesulfonate in the presence of anhydrous zinc chloride andtetrakis (triphenylphosphine) palladium (O) provides the titledaldehyde.

Ethyl-4-phenyl-3-furoate (Adapted from: Liotta, D.; Saindane, M.; Ott,W. Tet. Lett. (1983) 24, 2473.)

A mixture of 4-phenyloxazole 500 mg, 3.45 mmol) and ethyl phenylpropiolate (630 mg, 3.62 mmol) were heated in a sealed tube for 16 hoursat 210 degrees with stirring. The residue was filtered through silicausing 5% ethyl ether/hexanes to give the titled oxazole, 664 mg of apale oil, which was used without further purification. The starting4-phenyloxazole was prepared according to Bredereck, H.; Gompper, R.Chem. Ber. (1945), 87, 700.

4-Phenyl-3-furan methanol

LiAlH₄ (1.0M solution in hexane 1.14 ml, 1.14 mmol) was added dropwiseto a solution of ethyl-4-phenyl-3-furoate (246 mg, assumed 1.28 mmol) intetrahydrofuran (20 ml) at 0 degrees under argon. The solution wasstirred and was allowed to warm to room temperature gradually over 1/2hour. The mixture was quenched with saturated ammonium chloride and theorganics were extracted into ethyl ether, and washed with H₂ O.Evaporation of the dried (magnesium sulfate) extracts gave an oil, whichwas purified by flash chromatography on silica using 20% ethylacetate/hexanes. This was further purified by recrystallation(hexane/ethyl ether) to give the title compound as pale yellow crystals.

IR (CHCl₃): 3600 v. br., 3000 cm⁻¹.

¹ H NMR (CDCl₃): 1.90 (brs, 1H), 4.60 (brs, 2H), 7.22 to 7.60 (m, 7H).

¹³ C NMR (CDCl₃): 55.4, 124.1, 126.4, 127.4, 127.9, 128.9, 132.2, 140.4,142.3.

HRMS: exact mass calculated for C₁₁ H₁₀ O₂ (M⁺) 174.0680, found174.0696.

4-Phenyl-3-furaldehyde

A mixture of 4-phenyl-3-furanmethanol (458 mg, 2.63 mmol), powdered 4Amolecular sieves (500 mg), 4-methyl-morpholine-N-oxide (462 mg, 3.95mmol) and tetrapropylammonium perruthenate (46 mg, 0.13 mmol) inanhydrous dichloromethane (40 ml) were stirred at room temperature for 3hours. Residue was filtered through silica and concentrated to a brownoil which was purified by flash chromatography on silica using 10% ethylether/hexanes to give the titled aldehyde.

IR (CHCl₃): 3020, 1690 cm⁻¹.

¹ H NMR (CDCl₃): 7.30 to 7.55 (m, 5H); 7.59 (d, J=1.6 Hz, 1H); 8.15 d,J=1.6 Hz, 1H); 9.94 (s, 1H).

¹³ C NMR (CDCl₃): 125.8, 126.1, 128.0, 128.6, 128.7, 130.0, 142.0,152.6, 185.2.

HRMS: exact mass calculated for C₁₁ H₈ O₂ (M⁺) 172.0524 observed172.0520.

3(-1-Acetoxytridecyl)-4-phenylfuran

Dodecylmagnesium bromide (a 1.0M solution in THF; 2.11 ml, 2.11 mmol)was added to a solution of 4-phenyl-3-furaldehyde (303 mg, 1.76 mmol) inTHF at 0 degrees under argon and gradually allowed to warm to roomtemperature with stirring. When all of the aldehyde was consumed aceticanhydride (719 mg, 7.04 mmol) was added and stirring was continued for 2hours more. The reaction was quenched with saturated ammonium chlorideand the organics were extracted into ethyl ether. The combined fractionswere washed with saturated sodium bicarbonate, water and brine, driedover magnesium sulfate and concentrated to a yellow oil which waspurified by flash chromatography on silica using 3% ethyl ether hexanesto give the title compound.

IR (CHCl₃): 3020, 1725 cm⁻¹.

¹ H NMR (CDCl₃): 0.88 (t, J=6.6 Hz, 3H); 1.10 to 1.40 (m, 20H); 1.53 to1.78 (m, 2H); 2.00 (s, 3H); 5.92 (t, J=6.8 Hz, 1H); 7.27 to 7.46 (m,7H).

¹³ C NMR (CDCl₃): 13.8, 20.9, 22.4, 25.1, 28.9, 29.1, 29.26, 29.36,29.41, 31.7, 34.4, 68.5, 124.6, 126.3, 127.4, 128.6, 128.8, 132.4,140.6, 141.5, 170.5.

HRMS: exact mass calculated for C₂₅ H₃₆ O₃ (M⁺) 384.2667, observed384.2672.

4-(-1-Acetoxytridecyl)-5-hydroxy-3-phenyl-2(5H)-furanone

3-(-1-Acetoxytridecyl)-5-hydroxy-4-phenyl-2(5H)-furanone

A mixture of 3-(-1-acetoxytridecyl)-4-phenylfuran (506 mg, 1.32 mmol),water (a few drops) and Rose Bengal on polymer beads (1.6 g) in THF wasexposed to singlet oxygen at 0 degrees C. for 3 hours. The Rose Bengalwas filtered off and the residue was concentrated to a pink oil whichwas purified by flash chromatography on silica using 5 to 20% ethylacetate/hexanes to give the title furanones as a mixture of isomers. Theisomers were separated by HPLC chromatography on reverse phase Vydaccolumn using 15% water/acetonitrile.

3-(-1-acetoxytridecyl)-5-hydroxy-4-phenyl-2(5H)-furanone (retentiontime: 26.3 minutes).

IR (CDCl₃): 3020, 1760 cm⁻¹.

¹ H NMR (CDCl₃): 0.88 (t, J=6.7 Hz, 3H); 1.15 to 1.45 (m, 20H); 1.83 (s,3H); 1.77 to 1.92 (m, 1H); 1.92 to 2.07 (m, 1H); 5.59 (d, J=5.4 Hz 0.5H); 5.62 (d, J=5.4 Hz, 0.5 H); 6.31 (s, 1H); 7.40 to 7.54 m(5H).

¹³ C NMR (CDCl₃): 13.9, 20.3, 22.5, 25.4, 28.9, 29.16, 29.23, 29.3429.41, 29.45, 31.7, 32.6, 68.9, 97.6, 128.5, 128.7, 128.9, 130.2, 130.4,157.9, 169.6, 171.1.

LRMS m/z calculated for C₂₅ H₄₀ O₅ (M+NH₄)=434. Observed 434.

4-(-1-acetoxytridecyl)-5-hydroxy-3-phenyl-2(5H)-furanone (retention time28.0 minutes).

IR (CHCl₃): 3010, 1765 (v. br.)cm⁻¹.

¹ H NMR (CDCl₃): 0.88 (t, J=6.5 Hz, 3H); 1.12 to 1.40 (m, 20H); 1.81 (s,3H); 170 to 185 (m, 1H); 1.85 to 2.00 (m, 1H); 5.62 (d, J=5.1 Hz, 0.5H); 5.65 (d, J=5.0 Hz, 0.5 H); 6.17 (s, 1H); 7.33 to 7.50 (m, 5H).

¹³ C NMR (CDCl₃): 13.8, 20.1, 22.4, 25.3, 28.8, 29.1, 29.2, 29.3, 29.4,31.7, 33.0, 70.3, 97.2, 128.6, 128.9, 129.4, 131.1, 156.8, 170.7, 171.3.

LRMS m/z calculated for C₂₅ H₄₀ O₅ (M+NH₄)-434, observed 434.

2-Methyl-4-phenyl-3-furaldehyde

n-Butyllithium (a 1.6 m solution in hexane, 2.43 ml, 3.89 mmol) wasadded to a solution of trimethylethylenediamine (397 mg, 3.89 mmol) intetrahydrofuran (25 ml) at 0 degrees under argon. After 20 minutes thesolution was cooled to -78 degrees and 4-phenyl-3-furaldehyde (608 mg,3.35 mmol) was added. This mixture was allowed to gradually warm to -20degrees and stirred for 11/2 hours, then recooled to -78 degrees beforen-butyllithium (a 1.6M solution in hexane, 2.43 ml, 3.89 mmol) was addeddropwise. The stirring mixture was again gradually warmed to -20 degreesand stirred for 2 hours before iodomethane (2.56 g 17.67 mmol) wasadded. After stirring for 18 hours at -20 degrees the reaction wasquenched with ice-cold 10% (v/v) hydrochloric acid and the organics wereextracted into ethyl ether. The combined fractions were washed withsaturated sodium bicarbonate, H₂ O and brine. Evaporation of the dried(magnesium sulfate) extracts gave an oil which was purified by flashchromatography on silica using 20% ethyl ether/hexanes to give the titlealdehyde.

IR (CHCL3): 3600, 1690 cm⁻¹.

¹ H NMR (CDCl₃): 2.65 (s, 3H); 7.30 to 7.50 (m, 6H); 1.02 (s, 1H).

¹³ C NMR (CDCl₃): 13.4, 119.8, 127.2, 128.0, 128.7, 129.0, 130.6, 138.3,162.3, 186.7.

HRMS: exact mass calculated for C₁₂ H₁₀ O₂ (M⁺) 186.0680, found186.0689.

2-Methyl-4-phenyl-3-furanmethanol

LiAlH₄ (1.0M solution in hexane, 0.12 ml, 0.12 mmol) was added dropwiseto a solution of 2-methyl-4-phenyl-3-furaldehyde (45 mg, 0.24 mmol) intetrahydrofuran (3 ml) at 0 degrees under argon. After 10 minutes thereaction was quenched with saturated ammonium chloride and the organicswere extracted into ethyl ether. The combined fractions were washed withH₂ O and brine and the dried (magnesium sulfate) extracts wereconcentrated to a yellow oil which was carried on without furtherpurification.

IR (CHCl₃): 3620, 3450 (v. broad), 3005 cm⁻¹.

1H NMR (CDCl₃): 2.38 (S, 3H); 4.56 (s, 2H); 7.25 to 7.60 (m, 6H);

¹³ C NMR (CDCl₃): 11.5, 54.8, 117.9, 127.2, 127.5, 128.1, 128.9, 132.7,137.4, 151.9.

HRMS exact mass calculated for C₁₂ H₁₂ O₂ (M⁺) 188.0837, found 188.0850.

3-Dodecoyloxymethyl-2-methyl-4-phenylfuran

To a stirred solution of 2-methyl-4-phenyl-3-furanmethanol (48 mg, 0.26mmol) and triethylamine (39 mg. 0.38 mmol) in tetrahydrofuran (3 ml) at0 degrees under argon was added lauroyl chloride (73 mg. 0.33 mmol).This solution was warmed gradually to room temperature and stirred for41/2 hours. The organics were extracted into ethyl ether and washed witha 5% aqueous sodium bicarbonate solution, H₂ O and brine. Evaporation ofthe dried (magnesium sulfate) extracts gave an oil which was purified byflash chromatography on silica using 3% ether/hexanes to give the titlecompound.

IR (CHCl₃): 3010, 1725 cm⁻¹.

¹ H NMR (CDCl₃): 0.86 (t, J=6.7 Hz, 3H); 1.20 to 1.32 (m, 16H); 1.50 to1.64 (m, 2H); 2.23 to 2.32 (m, 2H); 2.36 (s, 3H); 4.97 (s, 2H); 7.29 to7.42 (m, 6H).

¹³ C NMR (CDCl₃): 11.7, 13.9, 22.5, 24.7, 28.9, 29.06, 29.12, 29.3,29.4, 31.7, 34.2, 56.5, 113.7, 127.3, 127.9, 128.1, 128.8, 132.5, 137.6,153.3, 174.1.

4-Dodecoyloxymethyl-5-hydroxy-5-methyl-3-phenyl-2-furanone (Compound185)

A mixture of 3-dodecoyloxymethyl-2-methyl-4-phenylfuran (40 mg, 0.11mmol), water (a few drops) and Rose Bengal on polymer beads (240 mg) intetrahydrofuran (40 ml) was exposed to singlet oxygen at 0 degrees for 3hours. The Rose Bengal was filtered off and the residue was concentratedto a pink oil which was purified by flash chromatography on silica using15% ethyl acetate/hexanes. The furanone was further purified by HPLCchromatography on a normal phase partisil 10 column using 15% ethylacetate/hexanes to give the title compound.

IR (CHCl₃): 3020, 1765, 1740 cm⁻¹.

¹ H NMR (CDCl₃): 0.85 (t, J=6.7 Hz, 3H): 1.10 to 1.21 (m, 16H); 1.35 to1.49 (m, 2H); 1.77 (s, 3H); 2.11 (t, J=7.6 Hz, 2H); 3.70 to 3.90 (brs,1H); 5.02 (s, 2H); 7.37 to 7.50 (m, 5H).

¹³ C NMR (CDCl₃): 13.9, 22.5, 24.0, 24.4, 28.9, 29.0, 29.1, 29.2, 29.4,31.7, 33.6, 57.2, 104.4 128.4, 128.7, 129.4, 129.8, 131.4, 154.4, 169.0,173.9.

HRMS: exact mass calculated for C₂₄ H₃₅ O₅ (MH⁺) 403.2484, found403.2497.

5-Methyl-2-triethylsilyl-4-furanmethanol

LiAlH₄ (1.0M solution in hexane, 0.51 ml, 0.51 mmol) was added dropwiseto a solution of 5-methyl-2-triethylsilyl-4-furaldehyde (230 mg, 1.03mmol) in tetrahydrofuran (15 ml) at 0 degrees under argon. The stirringsolution was allowed to warm to room temperature gradually over 1/2hour. The reaction was quenched with 10% aqueous HCl and the organicswere extracted into ethyl ether. The combined fractins were washed withH₂ O and brine. Evaporation of the dried (magnesium sulfate) extractsgave an oil which was purified by filtration through silica using 10%ethyl ether/hexanes to give the title compound.

IR (CHCl₃): 3610 (sharp), 3440 (broad), 2940 cm⁻¹.

¹ H NMR (CDCl₃): 0.71 (q, J=7.7 Hz, 6H); 0.96 (t, J=7.7 Hz, 9H); 2.25(s, 3H); 2.40 (brs, 1H); 4.38 (s, 2H); 6.59 (s, 1H).

¹³ C NMR (CDCl₃): 2.9, 11.5, 56.2, 118.9, 122.3, 153.7, 156.0.

4-Dodecoyloxymethyl-5-methyl-2-triethylsilylfuran

To a stirred solution of 5-methyl-2-triethylsilyl-4-furanmethanol (208mg. 0.92 mmol) and triethylamine (121 mg, 1.20 mmol) in tetrahydrofuran(10 ml) at 0 degrees under argon was added lauroyl chloride 302 mg, 1.38mmol). This solution was allowed to warm gradually to room temperatureand quenched with a 10% aqueous HCl solution. The organics wereextracted into hexanes and the combined fractions were washed with asaturated aqueous solution of sodium bicarbonate, H₂ O and brine.Evaporation of the dried (magnesium sulfate) extracts gave an oil whichwas purified by filtration through silica using 2% ethyl ether/hexanesto give the title compound.

IR (CHCl₃): 1725 cm⁻¹.

¹ H NMR (CDCl₃): 0.75 (q, J=7.7 Hz, 6H); 0.88 (t, J=6.7 Hz, 3H), 0.98(t, J=7.7 Hz, 9H); 1.20 to 1.35 (m, 16H); 1.56 to 1.68 (m, 2H); 2.30 (t,J=7.5 Hz, 2H); 2.31 (s, 3H); 4.91 (s, 2H); 6.57 (s, 1H).

¹³ C NMR (CDCl₃): 2.9, 7.0, 11.7, 13.8, 22.6, 24.8, 28.9, 29.08, 29.14,29.3, 29.4, 31.7, 34.2, 57.9, 114.7, 122.9, 155.3, 156.3, 174.2.

4-Dodecoyloxymethyl-5-hydroxy-5-methyl-2-furanone (Compound 186)

A mixture of 4-dodecoyloxymethyl-5-methyl-2-triethylsilylfuran (180 mg.0.44 mmol), water (a few drops) and Rose Bengal on polymer beads (360mg) in tetrahydrofuran (70 ml) was exposed to singlet oxygen at 0degrees until no starting material was visible (via TLC). The RoseBengal was filtered off and the residue was concentrated to a pink oilwhich was purified by flash chromatography on silica using 30% ethylacetate/hexanes to give the titled furanone.

IR (CHCl₃): 3400 (v. broad), 1750 (strong) cm⁻¹.

¹ H NMR (CDCl₃): 0.88 (t, J=6.7 Hz 3H); 1.20 to 1.37 (m, 16H); 1.59 to1.70 (m, 2H); 1.72 (s, 3H); 2.40 (t, J=7.6 Hz, 2H); 3.20 to 4.40 (v.brs, 1H); 4.93 (s, 2H); 5.94 (s, 1H).

¹³ C NMR (CDCl₃): 13.8, 22.4, 23.7, 24.5, 28.8, 28.9, 29.0, 29.2, 29.3,31.6, 33.7, 58.4, 105.9, 117.0, 166.2, 170.3, 173.7.

3-Phenyl-2-triethylsilyl-4-furaldehyde

n-Butyllithium (a 1.42M solution in hexane, 2.33 ml, 3.31 mmol) wasadded to a solution of 1-methylpiperazine (331 mg. 3.31 mmol) intetrahydrofuran (15 ml) at 0 degrees under argon. After 15 minutes thesolution was cooled to -78 degrees and 4-phenyl-3-furaldehyde (517 mg,3.01 mmol) was added. This mixture was warmed to 0 degrees and stirredfor 15 minutes, then recooled to -78 degrees before sec-butyllithium (a1.3M solution in cyclohexane, 2.77 ml, 3.61 mmol) was added dropwise.This solution was stirred 12 hours at -78 degrees C. beforechlorotriethylsilane (1.81 g, 12.02 mmol) was added. The mixture wasallowed to warm gradually to room temperature and stirred an additional11/2 hours. The reaction was quenched with ice-cold 5% (V/V)hydrochloric acid and the organics were extracted into ethyl ether. Thecombined fractions were washed with saturated sodium bicarbonate, H₂ Oand brine. Evaporation of the dried (magnesium sulfate) extracts gave anoil which was purified by flash chromatography on silica using 10% ethylacetate/hexanes to give the title aldehyde.

IR (heat): 2952, 1691 cm:

¹ H NMR (CDCl₃): 0.62 (q, J=7.8 Hz, 6H); 0.85 (t, J=7.8 Hz, 9H); 7.20 to7.43 (m, 5H); 8.30 (s, 1H); 9.79 (s, 1H).

¹³ C NMR (CDCl₃): 3.0, 6.8, 127.1, 128.2, 130.2, 131.8, 136.5, 153.7,158.3, 186.1.

3-Phenyl-2-triethylsilyl-4-furanmethanol

LiAlH₄ (1.0M solution in hexane, 1.48 ml, 1.48 mmol) was added dropwiseto a solution of 3-phenyl-2-triethylsilyl-4-furaldehyde (422 mg, 1.48mmol) in tetrahydrofuran (10 ml) at 0 degrees under argon. This mixturewas warmed to room temperature, quenched with ice-cold 5% (V/V)hydrochloric acid and the organics were extracted into ethyl ether. Thecombined fractions were washed with saturated sodium bicarbonate, H₂ Oand brine. The dried extracts (magnesium sulfate) were concentrated toan oil which was purified by flash chromatography on silica using 20%ethyl acetate/hexanes to give the title compound. IR (neat): 3300(broad); 2953 cm⁻¹.

¹ H NMR (CDCl₃): 0.59 (q, J=8.0 Hz, 6H); 0.85 (t, J=8.0 Hz, 9H); 1.60(brs, 1H); 4.42 (brs, 2H); 7.29 to 7.40 (m, 5H); 7.68 (s, 1H).

¹³ C NMR (CDCl₃): 3.2, 6.9, 55.2, 125.2, 127.6, 128.2, 130.0, 133.7,137.5, 144.9, 155.7.

4-Dodecoyloxymethyl-3-phenyl-2-triethylsilylfuran

To a stirred solution of 3-phenyl-2-triethylsilyl-4-furanmethanol (345mg, 1.20 mmol) and triethylamine (182 mg, 1.80 mmol) in tetrahydrofuran(15 ml) at 0 degrees under argon was added lauroyl chloride (786 mg,3.60 mmol). This solution was allowed to warm gradually to roomtemperature. After stirring an additional 2 hours the white precipitatewas filtered off. The filtrate was taken up into ethyl ether, washedwith saturated ammonium chloride, saturated sodium bicarbonate, H₂ O andbrine. Evaporation of the dried (magnesium sulfate) extracts gave an oilwhich was purified by flash chromatography on silica using 2% ethylether/hexanes to give the title compound.

IR (neat): 1737 cm⁻¹.

¹ H NMR (CDCl₃): 0.60 (q, J=8.1 Hz, 6H); 0.81 to 0.93 (m, 12H), 1.19 to1.35 (m, 16H); 1.48 to 1.61 (m, 2H); (m, 2H); 2.23 (t, J=7.5 Hz, 2H);4.86 (s, 2H); 7.25 to 7.40 (m, 5H); 7.72 (S, 1H).

¹³ C NMR (CDCl₃) 3.17, 6.90, 13.8, 22.5, 24.7, 28.9, 29.0, 29.1, 29.2,29.4, 31.7, 34.1, 56.4, 120.5, 127.6, 128.1, 130.1, 133.3, 138.0, 146.4,155.6, 173.8.

4-Dodecoyloxymethyl-5-hydroxy-3-phenyl-2(5H)-furanone

A mixture of 4-dodecoyloxymethyl-3-phenyl-2-triethylsilylfuran (256 mg,0.54 mmol), water (a few drops) and Rose Bengal on polymer beads (1.0 g)in tetrahydrofuran was exposed to singlet oxygen at 0 degrees for 3hours. The Rose Bengal was filtered off and the residue was concentratedto a pink oil which was purified by flash chromatography on silica using20% ethyl acetate/hexanes to give the title compound.

IR (CHCl₃): 3400 (v. broad), 1743 cm⁻¹.

¹ H NMR (CDCl₃): 0.88 (t, J=6.6 Hz, 3H); 1.05 to 1.45 (m, 16H); 1.50 to1.63 (m, 2H); 2.25 (t, J=7.6 Hz, 2H); 5.04 (S, 1H); 5.07 (S, 1H); 5.37to 5.50 (brs, 1H); 6.22 (S, 1H); 7.40 to 7.54 (m, 5H).

¹³ C NMR (CDCl₃): 14.1, 22.6, 24.6, 29.0, 29.2, 29.3, 29.4, 29.5, 31.8,33.8, 57.5, 96.5, 96.6, 128.1, 128.6, 129.1, 129.6, 131.7, 152.6, 170.5,173.6.

Example 18 ##STR43##

Compounds which are preferred in the method of treatment of the presentinvention and which are shown by Formula 21 above have the followingpreferred substituents. With respect to the 5-position of the furanonemoiety the preferred compounds are those where the substituent ishydroxy (in Formula 21 R₁ is H), acetoxy (R₁ is COCH₃), or where R₁ isCONHR₂ and R₂ is lower alkyl or phenyl, more preferably phenyl.

With reference to the length of the alkyl chain which connects the two5-hydroxy-2(5H)-furanone rings of the compounds of Formula 21, the alkylchain may contain between approximately 10 to 16 carbons (n is aninteger between 8 to 14); particularly preferred are the compounds wherethe chain has 12 or 14 carbons (n is 10 or 12).

With reference to the Y substituent, compounds are preferred where Y isH, straight or branch chained lower alkanoyl having 1 to 6 carbons, andwhere Y is CONHR₃, particularly where R₃ is phenyl.

Examples of preferred compounds of the invention are listed below withreference to Formula 21,

Compound 200 n=12, Y=CH₃ --CO, R₁ =H;

Compound 201 n=10, Y=NH--Ph--CO, R₁ =H;

Compound 202 n=12, Y=C(CH₃)₃ --CO, R₁ =H;

Compound 203 n=12, Y=C(CH₃)₃ --CO, R₁ =CONH--Ph.

The compounds of Example 18 can be made in accordance with the syntheticchemical pathways illustrated by the following specific examples. Thepracticing synthetic organic chemist can readily modify the chemicalpathways provided by these specific reactions and examples to prepareany and all compounds represented by Formula 21.

1,14-Diacetoxy-1,14-bis(2-Triethylsilyl-4 -furyl)tetradecane

2-Triethylsilyl-4-furaldehyde (530 mg, 2.52 mmol) was added to asolution of 1,12-dodecylmagnesium bromide (1.26 mmol; prepared from 414mg 1,12-dibmmododecane and 77 mg magnesium twinings) in THF (3 ml) at 0°C. under argon. When all the aldehyde was combined, acetic anhydride(0.71 ml, 7.57 mmol) was added. After stirring at room temperature for14 hours the mixture was quenched with water. Extraction (ethyl ether)and evaporation of the dried (magnesium sulfate) extracts gave an oil,which was purified by flash chromatography on silica using (10% ethylether/hexane to give the titled ester. IR (CHCl₃) 1725.

¹ HNMR (CDCl₃) 0.76 (t, 12H, J=7.6 Hz), 0.98 (t, 18H, J=7.6 Hz), 1.24(br, 20H), 1.95 (m, 4H), 2.04 (s, 6H), 5.78 (t, 2H, J=7.3 Hz), 6.59 (s,2H) and 7.60 (s, 2H).

¹³ C NMR (CDCl₃) 2.87, 6.94, 21.0, 25.2, 27.1, 29.0, 29.2, 29.3, 29.4,32.7, 34.6, 63.3, 68.5, 119.8, 125.0, 144.7, 159.5 and 178.

HRMS exact mass calculation for C₃₈ H₆₆ O₆ Si₂ (M⁺), 674.4398, found674.4389.

1,14-Diacetoxy-1,14-bis[5-hydroxy-2(5H)-4-furanoyl]tetradecane Compound200

A mixture of 1,14-diacetoxy-1,14-bis(2-triethylsilyl-4-furyl)tetradece(298 mg, 0.43 mmol) Rose Bengal (ca. 5 mg) and water (1 ml) in acetone(20 ml) was exposed to singlet oxygen at 0° C. for 4 hours. Onevaporation, the residue was purified by a silica column using 60% ethylacetate/hexane to give the desired furanone. IR(CHCl₃) 3400 and1750-1850.

¹ HNMR (CDCl₃) 1.25 (brs+m, 20H), 1.80 (m, 4H), 2.16 (s, 6H), 5.50 (brt,2H), 5.70 (brs, 1H), 5.92 (brs, 2H) and 5.10 (br, 2H).

¹³ CNMR 21.0, 25.0, 29.2, 29.4, 29.6, 29.7, 33.1, 69.7, 69.9, 70.0,98.6, 118.9, 119.0, 119.1, 119.3, 119.4, 167.7, 171.2 and 171.7.

LRMS m/e (% abundance) 510 (M⁺, 22) 468 (100), 451 (41), 408 (87), 391(55), 390 (45), 364 (22) and 347 (19).

1,12-Di(N-phenylcarbamoyl-1,12-bis(2-triethylsilyl-4-furyl)dodecane

2-Triethylsilyl-4-furaldehyde (100 mg, 0.5 mmol) was added to1,10-dodecylmagnesium bromide (1.13 mmol; prepared from 339 mg,1,10-dibromodecane and 61 mg magnesium twinings) in THF (1 ml) at 0° C.under argon. After the Grignard reagent was spent, phenyl isocyanate(0.26 ml, 2.38 mmol) was added. After stirring at room temperature for14 hours, the mixture was quenched with water. Extraction (ethyl ether)and evaporation of the dried (magnesium sulfate) extracts gave an oil,which was purified by flash chromatography on silica using ethylacetate/hexane to give the titled carbamate.

IR (CHCl₃) 3440, 1735 and 1608.

¹ H NMR (CDCl₃) (mixture of diasteromers) 0.75 (m, 12H), 0.95 (m, 18H),1.25 (m, 16H), 1.85 (m, 4H), 5.80 (t, 2H, J=6.9 Hz), 6.32 (s, 1H), 6.65(s, 1H), 6.8-7.65 (m, 10H), 7.61 (s, 1H) and 10.9 (br, 2H).

¹³ C NMR (CDCl₃) 2.78, 2.82, 6.93, 13.8, 22.4, 24.6, 25.2, 28.7, 28.8,29.0, 29.1, 29.2, 29.4, 31.3, 34.7, 69.5, 72.6, 118.7, 119.1, 119.7,120.0, 123.3, 124.0, 124.1, 124.9, 128.3, 128.8, 129.0, 137.3, 138.0,138.2, 144.2, 144.7, 151.7, 153.4, 155.6, 159.5 and 159.7.

LRMS (FAB) (m/e, % abundance) 823.43 [(M+Na)⁺, 0.1].

1,12-Di(N-phenylcarbamoyl)-1,12-bis[5-hydroxy-295H)-furano-4-yl]dodecane(Compound 201)

A mixture of1,12-di(N-phenylcarbamoyl)-1,12-bis(2-triethylsilyl-4-furyl)dodecane(250 mg. 0.31 mmol), Rose Bengal (ca. 3 mg) and water (1 ml) intetrahydrofuran (40 ml) was exposed to singlet oxygen at 0° C. for 6hours. On evaporation, the residue was purified by flash chromatographyon silica using 60% ethyl acetate/hexane to give the titled furanone. IR(CHCl₃) 3420, 3300, 1760, 1730, 1600 and 1525.

¹ HNMR (d₆ -acetone) (mixture of diasteromers) 1.30 (m, 16H), 1.90 (m,4H), 5.60 (br, 1H), 5.70 (br, 1H), 6.05, 6.45 (m, 4H), 7.00-7.65 (m,10H), 8.9 (br, 2H).

¹³ C NMR (d₆ -acetone) 25.3, 28.9, 29.2, 29.4, 29.7, 29.9, 30.0, 30.1,30.2, 33.4, 70.2, 71.0, 98.4, 98.5, 98.9, 99.0, 118.5, 119.4, 119.6,120.5, 120.6, 124.0, 124.8, 129.4, 129.9, 130.0, 130.1, 138.7, 139.3,140.1, 153.9, 169.1, 170.4, 170.8, 206.7 and 206.8.

HRMS exact mass calculated for C₃₄ H₄₁ N₂ O₁₀ 637.2761, found 637.2748.

1,14-Di(tert-butanoyloxy)-1,14-bis(2-triethylsilyl-4-furyl)tetradecane

2-Triethylsilyl-4-furaldehyde (1.05 g, 4.97 mmol) was added to1,12-dodecylmagnesium bromide (2.43 mmol; prepared from 0.79 g of1,12-dibromododecane and 127 mg magnesium twinings) in THF (10 ml) at 0°C. under argon. When all the furaldehyde was consumed,2,2-dimethylpropionyl chloride (0.69 ml, 5.58 mmol) was added. Stirringwas continued at room temperature for 14 hours and the mixture wasquenched with water. Extraction (ethyl ether) and evaporation of thedried (magnesium sulfate) extracts gave an oil, which was purified byflash chromatography on silica using 5% ethyl ether/hexane to give thetitled ester.

IR(CHCl₃) 1725.

¹ H NMR (CDCl₃) 0.75 (q, 12H, J=6.8 Hz). 0.97 (t, 18H, J=6.8 Hz), 1.24(m, 20H), 1.80 (m, 4H), 5.76 (t, 2H, J=7.8 Hz), 6.55 (s, 2H) and 7.56(s, 2H).

¹³ C NMR (CDCl₃) (CDCl₃) 3.14, 7.22, 25.3, 27.0, 29.2, 29.4, 29.5, 29.6,34.9, 38.7, 68.4, 119.6, 125.2, 143.9, 158.9 and 177.8.

1,14-Di(tert-butanoyloxy-1,14-bis[5-hydroxy-2(5H)-furans-4-yl]-tetradecane(Compound 202)

A mixture of1,14-di(tert-butanoyloxy)-1-,14-bis(2-triethylsilyl-4-furyl)tetra (990mg, 1.31 mmol), Rose bengal (5 mg) and water (1 ml) in acetone (70 ml)was exposed to singlet oxygen at 0° C. for 2 days. On evaporation, theresidue was purified on a silica column using 40% ethyl acetate/hexaneto give the desired furanone.

IR(CHCl₃) 3400 and 1730-1810.

¹ H NMR (CDCl₃) 1.25 (m, 38H), 1.80 (m, 4H), 6.25 (br, 2H), 5.40 (brt,2H), 5.91 (s, 2H) and 6.05 (br, 2H).

¹³ CNMR 24.6, 26.7, 26.8, 28.7, 28.8, 29.0, 29.1, 32.8, 38.7, 69.2,98.1, 111.5, 118.3, 118.4, 167.8, 170.4, 178.5 and 178.6.

HRMS (FAB) exact mass calculated for C₃₂ H₅₀ H₁₀ N_(a) (M+N_(a))⁺617.3302, found 617.3289.

1,14-Di-(tert-butanoyloxy)-1,14-bis[5-(N-phenylcarbanoyl-2(5H)-furano-4-yl]-tetradecane(Compound 203)

Phenyl isocyanate (0.10 ml, 0.93 mmol) was added to a mixture of1,14-di(tert-butanoyloxy)-1,14-bis[5-hydroxy-2(5H)-furano-4-yl]-tetradecane(Compound 202 277 mg, 0.47 mmol) and copper (I) chloride (92 mg, 0.93mmol) in N,N-dimethylformamide (3 ml) at 0° C. under argon. After 6hours at 0° C., the mixture was quenched with water and extracted withethyl acetate. The extracts were combined and washed successively withdilute HCl, saturated NaHCO₂ and brine. Evaporation of the dried(magnesium sulfate) organic phase gave an oil, which was purified byflash chromatography on silica using 30% ethyl acetate/hexane to givethe titled furanone.

IR (CHCl₃) 3340, 1810, 1770 and 1735.

¹ H NMR (CDCl₃), 1.30 (m, 38H), 1.80 (m, 4H), 5.65 (t, 2H, J=5.3 Hz),6.04 (s, 2H), 6.99 (s, 2H) and 7.00-7.50 (m, 10H).

HRMS (FAB) exact mass calculated for C₄₆ H₆₀ N₂ O₁₂ Na (M=Na)⁺ 855.4044,found 855.4077.

Example 19 ##STR44##

Compounds which are preferred in the method of treatment of the presentinvention and which are shown by Formula 22 above have the followingpreferred substituents.

With respect to the 5-position of the furanone moiety those compoundsare preferred in the method of treatment of the present invention wherethe substituent is hydroxy (in Formula 22 R₁ is H) or acetoxy (R₁ isCOCH₃).

With reference to the length of the alkyl chain (A) in the dicarboxylicacid residue (CO--A--CO) which connects the two(5-hydroxy-2(5H)-furano-yl)(1-hydroxy)alkyl or the two(5-hydroxy-2(5H)-furanoyl)(1amino)alkyl moieties of the preferredcompounds, the alkyl chain may contain between approximately 0 to 30carbons; preferably A is a straight chain divalent alkyl radicalrepresented by (CH₂)_(n) where n is an integer between 0 to 30, morepreferably between 0 to 16 carbons.

With reference to the alkyl substituent on the alpha carbon in the4-position of the furan nucleus of the preferred compounds (R₃ inFormula 22), the alkyl substituent may contain 5 to 20 carbons.Preferably the alkyl substituent (R₃) is n-alkyl, having 6 to 16carbons.

The most preferred compounds of the invention are listed below withcontinuing reference to Formula 22, where for the purposes of the listedexamples R₁ =H and A=(CH₂)_(n).

Compound 210: X=O, n=1, R₃ =--(CH₂)₁₁ CH₃ ;

Compound 211: X=O, n=3, R₃ =--(CH₂)₁₁ CH₃ ;

Compound 212: X=NH, n=3, R₃ =--(CH₂)₁₁ CH₃ ;

Compound 213: X=O, n=1, R₃ =--(CH₂)₅ CH₃ ;

The compounds of Example 19 can be made in accordance with the syntheticchemical pathways illustrated by the following specific examples. Thepracticing synthetic organic chemist can readily modify the chemicalpathways provided by these specific reactions and examples to prepareany and all compounds represented by Formula 22.

4-(1-Hydroxytridecyl)-2-triethylsilylfuran

Dodecylmagnesium bromide (a 1M solution in tetrahydrofuran; 14.3 ml;14.3 mmol) was added dropwise to a solution of2-triethylsilyl-4-furaldehyde (2.0 g, 9.52 mmol) in THF (20 ml) at 0degrees C. under argon. After stirring at room temperature for 2 hours,the mixture was quenched with dilute HCl and extracted with ethyl ether.Evaporation of the dried (magnesium sulfate) extracts gave an oil, whichwas purified by flash chromatography on silica using 30% ethylether/hexane to give the titled alcohol. ¹ HNMR (CDCl₃) 0.76 (q, 6H,J=8.0 Hz), 0.88 (t, 3H, J=6.3 Hz), 0.98 (t, 9H, J=8.0 Hz), 1.25 (m,20H), 1.62 (d, 1H, J=4.3 Hz), 1.75 (m, 2H), 4.63 (dd, 1H, J=6.6 Hz, 1.9Hz), 6.63 (s, 1H) and 7.57 (s, 1H).

Bis[1-(2-triethylsilyl-4-furyl)tridecyl]malonate

Malonyl dichloride (49 ul, 0.5 mmol) was added dropwise to a solution of4-(1-hydroxytridecyl)-2-triethylsilylfuran (0.40 g, 1.05 mmol) at 0degrees C. After 5 minutes, diisopropylethylamine (0.17 ml, 1.0 mmol)was added and stirring was continued at 0 degrees C. for 3 hours. Themixture was quenched with water and extracted with (ethyl ether).Evaporation of the dried (magnesium sulfate) extracts gave an oil, whichwas purified by flash chromatography on sillica using 7.5 ethylether/hexane to give the titled ester.

¹ HNMR (CDCl₃) 0.76 (q, 12H, J=8.0 Hz), 0.88 (t, 6H, J=6.9 Hz), 0.97 (t,18H, J=8.0 Hz), 1.25 (m, 40H), 1.80 (m, 4H), 3.36 (s, 2H), 5.82 (t, 2H,J=6.6 Hz), 6.58 (s, 2H) and 7.60 (s, 2H).

¹³ C NMR (CDCl₃) 2.9, 7.0, 13.8, 22.5, 25.2, 29.0, 29.2, 29.3, 29.4,29.5, 31.7, 34.4, 42.0, 69.9, 119.7, 124.4, 144.9, 159.6 and 166.3

LRMS (FAB) 851.6 (M+Na⁺).

Bis[1-(5-hydroxy-2(5H)-furano-4-yl)tridecyl]malonate (Compound 210)

A mixture of bis[1-(2-triethylsilyl-4-furyl)tridecyl]malonate (226 mg,0.27 mmol), Rose Bengal (5 mg) said water (1 ml) in acetone (20 ml) wasexposed to singlet oxygen at 0 degrees C. for 7 hours. On evaporation,the residue was purified by flash chromatography on silica using 40%ethyl acetate/hexane to give the titled furanone.

IR (CHCl₃) 3400 and 1765.

¹ HNMR (CDCl₃) 0.68 (t, 6H, J=7.0 Hz), 1.26 (m, 40H), 1.85 (br, 4H),3.56 (br, 2H), 5.68 (br, 1H), 5.76 (br, 1H), 6.04 (s, 2H), 6.06 (s, 1H)and 6.25 (brs, 1H).

¹³ C NMR (CDCl₃) 13.8, 22.4, 24.7, 28.9, 29.1, 29.2, 29.3, 29.4, 31.7,32.6, 40.6, 40.8, 70.4, 70.5, 71.2, 98.1, 118.8, 119.8, 119.9, 165.8,166.3 and 171.0.

HRMS (FAB) exact mass calculated for C₃₇ H₆₀ O₁₀ Na 687.4084, found687.4091.

Di[1-(2-triethylsilyl-4-furyl)]tridecyl 1,5-pentandioate

n-Dodecylmagnesium bromide (a 1.0M solution in THF; 7.52 ml; 7.52 mmol)was added to a solution of 2-triethylsilyl-4-furaldehyde (1.58 g, 7.52mmol) in THF (20 ml) at 0 degrees C. under argon. The mixture was warmedto room temperature. When all the aldehyde was consumed, as shown byTLC, the mixture was recooled to 0 degrees C. and 1,5-pentandioylchloride (0.44 ml, 3.42 mmol) was added. Stirring was continued at roomtemperature overnight and the mixture was quenched with ammoniumchloride solution. Extraction (ethyl ether) and evaporation of the dried(magnesium sulfate) extracts gaven an oil. The crude product waspurified by flash chromatography (SiO₂, 5% ethyl ether/hexane) to givethe titled furan.

IR (CHCl₃) 1725;

¹ HNMR (CDCl₃) 0.75, (q, 12H, J=7.5 Hz), 0.88 (t, 6H, J=6.9 Hz), 0.94(t, 18H, J=7.5 Hz), 1.25 (brs, 40H), 1.80 (m, 4H), 1.95 (p, 2H, J=6.2Hz), 2.33 (t, 4H, J=6.2 Hz), 5.80 (t, 2H, J=7.5 Hz), 6.58 (s, 2H) and7.59 (s, 2H).

¹³ C NMR (CDCl₃) 2.89, 6.99, 13.8, 20.1, 22.5, 25.3, 29.1, 29.2, 29.3,29.4, 31.7, 33.4, 34.6, 68.6, 119.7, 124.9, 144.7, 159.5 and 172.7.

4-(1-Azidotridecyl)-2-triethylsilylfuran

A solution of diphenylphosphozylazide (143 mg, 0.52 mmol) in THF (2 ml)was added over a period of 15 minutes to a solution of4-(1-hydroxytridecyl)-2-triethylsilylfuran (200 mg, 0.52 mmol),triphenylphosphine (140 mg, 0.52 mmol) and diethyl azidocarboxylate (90mg, 0.52 mmol) in THF (10 ml) at room temperature. After stirring for 2days, the mixture was evaporated in the presence of a minimum amount ofsilica gel. The residue was purified by flash chromatography on silicausing 5% ethyl ether/hexane to give the titled azide.

¹ HNMR (CDCl₃) 0.77 (q, 6H, J=8.0 Hz), 0.88 (t, 3H, J=6.4 Hz), 0.98 (t,9H, J=8.0 Hz), 1.25 (m, 20H), 1.75 (m, 2H), 4.33 (t, 1H, J=7.5 Hz), 6.60(s, 1H) and 7.61 (s, 1H).

4-(1-Aminotridecyl)-2-triethylsilylfuran

A solution of lithium aluminum hydride (a 1.0M solution in THF; 4.22 ml,4.22 mmol) was added slowly to a solution of4-(1-azidotridecyl)-2-triethylsilylfuran (1.55 g, 3.84 mmol) at 0degrees C. under argon. After stirring at room temperature for 2 hours,the mixture was cooled to 0 degrees C. and quenched with 2M sodiumhydroxide. Anhydrous sodium sulfate was added to coagulate the aluminumsalt and the mixture was extracted thoroughly with ethyl acetate.Evaporation of the dried (magnesium sulfate) extracts gave an oil, whichwas purified by flash chromatography on silica using 5%methanol/dichloromethane to give the titled amine.

¹ H NMR (CDCl₃) 0.76 (q, 6H, J=8.0 Hz), 0.88 (t, 3H, J=6.5 Hz), 0.98 (t,9H, J=8.0 Hz), 1.25 (m, 20H), 1.80 (m, 2H), 3.95 (t, 1H, J=6.8 Hz), 6.60(s, 1H) and 7.50 (s, 1H).

N,N'-bis[2-triethylsilyl-4-furyl)tridecyl]-1,5-pentadiamide

1,5-Pentanoyl dichloride (50 ul, 0.39 mmol), followed by triethylamine(0.11 ml, 0.79 mmol) was added to a solution of4-(1-aminotridecyl)-2-triethylsilylfuran (142 mg, 0.38 mmol) indichloromethane at room temperature. After stirring for 15 hours, themixture was quenched with water and extracted with ethyl ether.Evaporation of the dried (magnesium sulfate) extracts gave an oil, whichwas purified by flash chromatography to give the titled amide. R_(f)(50% ethyl ether/hexane) 0.09

¹ H NMR (CDCl₃) 0.74 (q, 12H, J=7.9 Hz) 0.89 (t, 6H, J=6.8 Hz), 0.98 (q,18H, J=7.9 Hz), 1.26 (brs, 40H), 1.70 (brm, 4H), 2.0 (m, 2H), 2.25 (m,4H), 5.0 (q, 2H, J=7.5 Hz), 5.58 (m, 2H), 6.55 (s, 2H), 7.53 (s, 1H) and7.54 (s, 1H).

N,N'-bis[1-(5-hydroxy-2(5H)-furanon-4-yl)tridecyl]-1,5-pentadiamide(Compound 212)

Singlet oxygen oxidation ofN,N'-bis[triethylsilyl-4-furyl)tridecyl]-1,5-pentadiamide, under theusual condition, gave the titled furanone.

Di[1-(5-hydroxy-2(5H)-furanon-4-yl)]tridecyl 1,5-pentandioate (Compound211)

A mixture of di[1-(2-triethylsilyl-4-furyl)]tridecyl 1.5-pentandioate(1.98 g, 2.32 mmol), Rose Bengal (ca, 5 mg) and water 2 ml) in THF (150ml) was exposed to singlet oxygen at 0 degrees C. for 7 hours. Theresidue, after evaporation, was purified by flash chromatography (SiO₂,30% ethyl acetate/hexane) to give the titled furanone.

IR (CHCl₃) 3500-3300, 1750; 3

¹ HNMR (CDCl₃) 6.89 (t, 6H, J=6.8 Hz), 1.27 (brm, 40H), 1.83 (m, 4H),1.99 (m, 2H), 2.44 (t, 4H, J=6.9 Hz), 5.57 (t, 2H, J=6.2 Hz), 5.85 (br,2H), 6.00 (s, 1H), 6.02 (s, 1H) and 6.15 (br, 2H).

¹³ C NMR (CDCl₃) 13.8, 19.4, 19.6, 22.5, 24.9, 29.0, 29.1, 29.2, 29.4,29.5, 31.8, 32.8, 32.9, 69.7, 98.4, 118.9, 119.0, 119.1, 119.3, 166.9,167.0, 170.8, 170.9 and 173.1.

Di[(1-2-triethylsilyl-4-furyl)heptyl]malonate

Using the same procedure as for di[1-2(triethylsilyl-4-furyl)]-tridecyl1,5-pentandioate except using hexyl magnesium bromide and malonyldichloride instead of dodecylmagnesium bromide and 1,5-pentanoyldichloride respectively, the title compound was obtained.

IR (CHCl₃) 1740, 1725

¹ H NMR (CDCl₃) 0.77 (q, 12H, J=7.5 Hz), 0.87 (t, 6H, J=6.8 Hz), 0.96(t, 18H, J=7.5 Hz), 1.26 (brs, 20H), 3.56 (s, 2H), 5.83 (t, 2H, J=7.4Hz), 6.58 (s, 2H) and 7.59 (s, 2H)

¹³ C NMR (CDCl₃) 2.89, 6.98, 13.7, 22.3, 25.1, 28.7, 31.4, 34.4, 41.9,69.9, 119.7, 124.5, 144.9, 159.6 and 166.3.

Di[(1-5-hydroxy-2(5H) -furanon-4-yl)heptyl]malonate (Compound 213)

A mixture of di[(1-2-triethylsilyl-4-furyl)heptyl]malonate (680 mg, 1.37mmol) Rose Bengal (ca, 5 mg) and water (1 ml) in acetone (100 ml) wasexposed to singlet oxygen at 0 degrees C. for 7 hours. The residue,after evaporation, was purified by flash chromatography (SiO₂, 30% ethylacetate/hexane) to give the titled furanone.

IR (CHCl₃) 3500-3300, 1800-1720

¹ H NMR (CDCl₃) 0.88 (t, 6H, J=6.9 Hz), 1.25 (brm, 12H), 1.83 (m, 4H),3.53 (brm, 2H), 5.25 (br, 2H), 5.65 (t, 2H, J=5.9 Hz) and 6.06 (brs, 4H)

¹³ C NMR (CDClv3v) 13.7, 22.3, 24.6, 28.5, 31.3, 32.5, 40.7, 40.8, 60.5,70.6, 70.7, 70.8, 70.9, (br), 98.2, 118.8, 118.9, 119.0, 119.7, 166.2and 170.9.

Example 20 ##STR45##

Compounds which are preferred in the method of treatment of the presentinvention and which are shown by Formula 23 above have the followingpreferred substituents. With respect to the 5-position of the furanonemoiety, those compounds are preferred where the substituent is hydroxy(in Formula 1 R₁ is H), acetoxy (R₁ is COCH₃), 2,2-dimethylpropionyloxy(R₁ is CH₃ --C(CH₃)₂ --CO) or where R₁ is CONHR₂ and R₂ is lower alkylor phenyl, more preferably phenyl.

With reference to the length of the alkyl chain (A) which connects thetwo (5-hydroxy-2(5H)-furanoyl)methanol or the two(5-hydroxy-2(5H)-furanoyl)methylamin moieties of the compounds, thealkyl chain may contain between approximately 5 to 30 carbons;preferably A is a straight chain divalent alkyl radical represented by(CH₂)_(n) where n is an integer between 5 to 30, more preferably between6 to 16 carbons.

Examples of preferred compounds are listed below with continuingreference to Formula 23. For the purposes of the listed examplesA=(CH₂)₁₀, and the two substituents on the 5-hydroxy group, that is thetwo R₁ groups are differentiated as R₁.spsb.' and as R₁.spsb.".

Compound 220 X=O, R₁.spsb.' =H, R₁.spsb." =H;

Compound 221 X=O, R₁.spsb.' =CH₃ --C(CH₃)₂ --CO, R₁.spsb." =CH₃--C(CH₃)₂ --CO;

Compound 222 X=NH, R₁.spsb.' =H, R₁.spsb." =H;

Compound 223 X=NH, R₁.spsb.' =CONH--phenyl, R₁.spsb.' =CONH--phenyl;

Compound 224 X=NH, R₁.spsb.' =H, R₁.spsb." =CONH--phenyl.

The compounds of Example 20 can be made in accordance with the syntheticchemical pathways illustrated by the following specific examples. Thepracticing synthetic organic chemist can readily modify the chemicalpathways provided by these specific reactions and examples to prepareany and all compounds represented by Formula 23.

4-Hydroxymethyl-2-trimethylsilylfuran

2-Trimethylsilyl-4-furaldehyde (1.57 g, 9.35 mmol) was added to asuspension of sodium borohydride (424 mg, 11.2 mmol) in methanol (10 ml)at 0° C. After 45 minutes, most of the methanol was evaporated and theresidue taken up in ethyl ether. The ethyl ether extracts were combined,washed (water), dried (magnesium sulfate) and evaporated to dryness togive an oil, which was purified by flash chromatography on silica using30% ethyl ether/hexane to give the title alcohol as a pale yellow oil.

¹ H NMR (CDCl₃): 7.57 (s, 1H); 6.64 (s, 1H); 4.50 (s, 2H); 2.75 (broads, 1H); 0.25 (s, 9H).

¹³ C NMR (CDCl₃): 161.5, 144.0, 125.0, 119.7, 56.2, -1.8.

HRMS exact mass calculated for C₈ H₁₄ O₂ Si: 170.0763, obtained (EI⁺):170.0766.

4-Hydroxymethyl-2-triethylsilylfuran

Sodium borohydride (353 mg, 0.93 mmol) was added portionwise to asolution of 2-triethylsilyl-4-furaldehyde (1.64 g, 7.79 mmol) inmethanol (10 ml) at 0°. After 1 hour, most of the methanol wasevaporated and the residue dissolved in a minimum amount of dilutehydrochloric acid. Extraction (ethyl acetate), drying (magnesiumsulfate) and evaporation gave an oil, which was purified by flashchromatography on silica using 20% ethyl ether/hexane. Fractions withR_(f) of about 0.07 (10% ethyl ether/hexane) gave after evaporation thetitle alcohol as a colorless oil.

¹ HNMR (CDCl₃) 0.76 (q, 6H, J=7.4 Hz), 0.97 (t, 9H, J=7.5 Hz), 1.45 (t,1H, J=5.3 Hz), 4.56 (d, 2H, J=5.3 Hz), 6.67 (s, 1H) and 7.62 (s, 1H).

HRMS exact mass calculated for C₁₁ H₂₀ SiO₂ (M⁺) 212.1233 found212.1231.

(E),(Z)-)-O-Methyl-2-triethylsilyl-4-furaldehyde oxime

A solution of sodium acetate (1 g, 12.3 mmol) and methoxylaminehydrochloride (1.05 g, 12.3 mmol) in water (5 ml) was added to asolution of 2-triethylsilyl-4-furaldehyde (860 mg, 4.1 mmol) in ethanol(6 ml) at room temperature. After stirring for 16 hours, most of theethanol was evaporated and the residue dissolved in water. Extraction(ethyl acetate) and evaporation of the dried (magnesium sulfate)extracts gave an oil, which was purified by flash chromatography onsilica using 5% ethyl ether/hexane to give the title oxime as acolorless oil.

¹ HNMR (CDCl₃) 0.79 (q, 6H, J=7.3 Hz), 0.99 (t, 9H, J=7.9 Hz), 3.95 (s,3H), 4.06 (s, 3H), 6.84 (s, 1H), 7.00 (s, 1H), 7.28 (s, 1H), 7.82 (s,1H), 8.05 (s, 1H) and 8.34 (s, 1H).

HRMS exact mass calculated for C₁₂ H₂₁ NO₂ Si(M⁺) 239.1341, found239.1332.

4-Aminomethyl-2-triethylsilylfuran

Lithium aluminum hydride (a 1.0M solution in tetrahydrofuran; 0.54 ml,0.54 mmol) was added dropwise to a solution of(E),(Z)-O-methyl-2-triethylsilyl-4-furaldehyde oxime (Compound 12, 106.2mg, 0.46 mmol) in tetrahydrofuran (5 ml) at room temperature. Afterstirring at room temperature overnight (ca. 14 hours), the reactionmixture was quenched with water. Extraction (ethyl ether) andevaporation of the dried (magnesium sulfate) extracts gave an oil, whichwas purified by flash chromatography on silica using 10%methanol/dichloromethane/1% ammonia. Fractions with R_(f) of about 0.34gave after evaporation the title amine as a pale yellow oil.

¹ H NMR (CDCl₃) 0.76 (q, 6H, J=7.9 Hz), 0.98 (t, 9H, J=8.4 Hz), 1.87 (brs, 2H), 3.76 (s, 2H), 6.63 (s, 1H) and 7.56 (s, 1H).

HRMS exact mass calculated for C₁₁ H₂₁ SiNO(M⁺) 211.1392, found211.1389.

Di-(2-triethylsilyl-4-furyl)methyl dodecan-1,12-dioate

1,12-Dodecanedioyl dichloride (0.44 ml, 1.74 mmol) followed bytriethylamine (0.51 ml, 3.65 mmol) was added to a solution of4-hydroxymethyl-2-triethylsilylfuran (756 mg, 3.57 mmol) in THF (10 ml)at 0 degrees C. After stirring at room temperature overnight, themixture was diluted with ethyl ether and washed successively withsaturated NaHCO₃, water and brine. Evaporation of the dried (magnesiumsulfate) organic phase gave an oil, which was purified on a silicacolumn using 3% ethyl ether/hexane to give the titled ester.

IR (neat) 1750.

¹ H NMR (CDCl₃) 0.73 (q, 12H, J=7.0 Hz), 0.95 (t, 18H, J=7.0 Hz), 1.22(br, 12H), 1.60 (m, 4H), 2.28 (t, 4H, J=7.0 Hz), 4.95 (s, 4H), 6.61 (s,2H) and 7.63 (s, 2H).

¹³ CNMR (CDCl₃) 2.84, 6.93, 24.7, 28.8, 29.0, 29.1, 34.1, 57.4, 77.4,120.4, 121.5, 145.9, 159.8 and 174.0

HRMS exact mass calculated for C₃₄ H₆₂ NO₆ Si₂ (M+NH₄)⁺ 636.4116, found636.4109.

Di-[5-hydroxy-2(5H)-2-oxo-4-furyl]methyl dodecan-1,12-dioate (Compound220)

A mixture of di-(2-triethylsilyl-4-furyl)methyl dodecan-1,12-dioate (977mg, 1.58 mmol), Rose Bengal (ca. 3 mg) and water (ca. 1 ml) in THF (150ml) was exposed to singlet oxygen at 0 degrees C. for 8 hours. Themixture was filtered and evaporated to dryness to give a solid, whichwas purified by flash chromatography on silica using 30% ethylacetate/hexane to give the titled bis-furanone.

IR (CHCl₃) 1750.

¹ HNMR (CDCl₃) 1.25 (brs, 12H), 1.55 (brm, 4H), 2.41 (t, 4H, J=7.4 Hz),4.92 (ddd, 4H, J=16.9 Hz, 1.7 Hz), 6.13 (brs, 4H) and 8.10 (br, 2H)

¹³ CNMR (CDCl₃) 24.2, 28.3, 28.6, 28.7, 33.1, 38.7, 38.9, 39.2, 39.4,39.8, 40.1, 40.3, 58.8, 97.7, 117.4, 165.1, 170.3 and 172.8.

HRMS exact mass calculated for C₂₂ H₃₁ O₁₀ (M+H)⁺ 455.1917, found455.1916.

Di-[5-tert-butanoyloxy-2(5H)-furano-4-yl]methyl dodecan-1,12-dioate(Compound 221)

Ethyl diisopropylamine (52 microliter,, 0.30 mmol), followed by2,2-dimethylpropionyl chloride (37 microliter, 0.30 mmol) was added to asolution of di-[5-hydroxy-2(5H)-furano-4-yl]methyl dodecan-1,12-dioate(59 mg, 0.13 mmol) in THF (2 ml) at 0 degrees C. under argon. Afterstirring at 0 degrees C. for 3 hours, the mixture was diluted with ethylether and washed successively with water, NaHCO₃ solution and brine.Evaporation of the dried (magnesium sulfate) organic layer gave an oil,which was purified by flash chromatography on silica using 20% ethylacetate/hexane to give the titled diester.

IR (CHCl₃) 1800, 1760

¹ HNMR (CDCl₃) 1.21 (s, 18H), 1.23 (br, 12H), 1.60 (m, 4H), 2.35 (t, 4H,J=7.7 Hz), 4.85 (brs, 4H), 6.13 (brs, 2H) and 6.91 (brs, 2H).

¹³ CNMR (CDCl₃) 24.5, 26.6, 28.8, 28.9, 29.1, 33.6, 38.8, 58.0, 92.6,119.9, 161.2, 169.1, 173 and 176.6.

HRMS, exact mass calculated for C₃₂ H₅₀ NO₁₂ (M+NH₄)⁺ 640.3333, found640.3312.

N,N'-Bis(2-triethylsilyl-4-furyl)methyl-1,12-dodecanoic acid amide

Diisopropylethylamine (0.46 ml, 2.65 mmol), followed by1,12-dodecanedioyl dichloride (0.32 ml, 1.26 mmol) was added to asolution of 4-aminomethyl-2-triethylsilylfuran (Compound 8, 533 mg, 2.53mmol) in dichloromethane at 0 degrees C. under argon. After stirring atroom temperature for 8 hours the mixture was quenched with water.Extraction (ethyl ether) and evaporation of the dried (magnesiumsulfate) extracts gave an oil which was purified by flash chromatographyon silica using 1% methanol/chloroform to give the titled amide.

IR (CHCl₃) 1675, 1625, 1510.

¹ HNMR (CDCl₃) 0.75 (q, 12H, J=7.9 Hz), 0.96 (t, 18H, J=7.9 Hz), 1.25(m, 12H), 1.65 (m, 4H), 2.18 (t, 4H, J=7.8 Hz), 4.24 (d, 4H, J=5.5 Hz),6.50 (brt, 2H), 6.58 (s, 2H) and 7.53 (s, 2H).

¹³ C NMR (CDCl₃) 2.72, 6.81, 20.3, 25.4, 28.8, 28.9, 29.0, 29.1, 33.8,36.2, 45.2, 121.2, 144.2, 159.5 and 173.3.

HRMS exact mass calculated for C₃₄ H₆₁ N₂ O₄ Si₂ (M+H)⁺ 617.4170, found617.4197.

N,N'-Bis(5-hydroxy-2(5H)-2-oxo-4-furyl)methyl-1,12-dodecanoic acid amide(Compound 222)

A mixture of N,N-bis (2-triethylsilyl-4-furyl)methyl-1,12-dodecanamide(463 mg, 0.75 mmol), Rose Bengal (ca, 3 mg) and water (1 ml) in THF (50ml) was exposed to singlet oxygen at 0 degrees C. for 5 hours. Themixture was filtered and the filtrate evaporated to dryness to give anoil, which was purified by flash chromatography on silica using 10%methanol/chloroform to give the titled furanone.

IR (CHCl₃) 1758, 1661 and 1548.

¹ H NMR (CD3OD) 1.23 (brs, 12H), 1.62 (brm, 4H), 2.26 (t, 4H, J=7.7 Hz),4.15 (brs, 4H), 5.89 (brd, 2H, J=1.0 Hz) and 6.09 (brs, 2H)

¹³ C NMR (CD3OD) 26.8, 30.2, 30.3, 30.4, 36.8, 37.6, 100.5, 100.6,118.5, 169.1, 173.1 and 177.0.

HRMS exact mass calculated for C₂₂ H₃₃ N₂ O₈ (M+H)⁺ 453.2236, found453.2247.

Bis-[(2-triethylsilyl-4-furyl)methyl]oxalate

Oxalyl chloride (0.59 ml, 6.79 mmol) was added dropwise to a solution of4-hydroxymethyl-2-triethylsilylfuran (1.2 q, 5.66 mmol) andtriethylamine (0.95 ml, 6.79 mmol) in dichloromethane (10 ml) at 0degrees. After 10 minutes, the reaction mixture was quenched with ice.Extraction (dichloromethane) and evaporation of the dried (magnesiumsulfate) extracts gave an oil, which was purified by flashchromatography on silica using 5% ethyl ether/hexane. Fractions withR_(f) of about 0.17 gave, after evaporation, the title oxalate ester asa colorless oil. (83%).

¹ HNMR (CDCl₃) 0.81 (q, 6H, J=7.3 Hz), 1.02 (t, 9H, J=7.3 Hz), 5.24 (s,2H), 6.73 (s, 1H) and 7.78 (s, 1H).

MS m/e (% abundance) 195(100), 167(16), 115(35) and 87(29).

Singlet oxygen oxidation of bis-[(2-triethylsilyl-4-furyl)methyl]oxalatein the presence of water, gives the corresponding bis-furanone.

N-(5-Hydroxy-2(5H)2-oxo-4-furyl)methyl-N'-(5-phenylcarbamoyloxy-2(5H)2-oxo-4-furyl)methyl-1,12-dodecanamide (Compound 223) andN,N'-bis(5-phenylcarbamoyloxy-2(5H)2-oxo-4-furyl)methyl-1,12-dodecanamide(Compound 224).

Phenyl isocyanate (29 microliter, 0.27 mmol) was added to a mixture ofN,N'-bis(5-hydroxy-2(5H)2-oxo-4-furyl)methyl-1,12-dodecanamide (Compound222, 116 mg, 0.26 mmol) and copper (I) chloride (27 mg, 0.27 mmol) inDMF (2 ml) at 0 degrees C. under argon. After stirring for 3 hours, themixture was quenched with water. Extraction (ethyl ether) andevaporation of the dried (magnesium sulfate) extracts gave an oil, whichwas purified by flash chromatography (10% methanol/chloroform) to givethe titled mono- and bis-carbamates. Mono-carbamate (Compound 223):R_(f) (10% methanol/chloroform) 0.21

IR (CHCl₃) 3600-3400, 1720 and 1530

¹ H NMR (CDCl₃) 1.27 (m, 12H), 1.60 (m, 4H), 2.25 (t, 4H, J=7.7 Hz),4.20 (m, 2H), 4.35 (m, 2H), 5.89 (brs, 1H), 6.11 (brs, 2H), 6.99 (s,1H), 7.05-7.60 (m, 5H) and 7.70 (m, 2H), LRMS (FAB) m/e (% abundance)594 [(M+Na)⁺, 20).

Bis-carbamate (Compound 224): R_(f) (10% methanol/chloroform) 0.37

IR (CHCl₃) 3700, 3500-3300, 1805, 1775, 1720, 1680, 1610 and 1540-1520

¹ HNMR (CDCl₃) 1.27 (m, 12H), 1.60 (m, 4H), 2.25 (t, 4H, J=7.9 Hz), 4.20(dd, 1H, J=17.4 Hz, 4.9 Hz), 4.35 (dd, 1H, J=17.4 Hz, 4.9 Hz), 6.01 (br,1H), 6.12 (s, 1H), 6.45 (br, 1H), 6.80 (t, 1H), 6.95 (brd, 1H), 6.99 (s,2H), 7.08 (t, 2H, J=7.6 Hz), 7.20 (t, 4H), 7.35 (m, 4H), 7.50 (brd, 4H),7.59 (m, 4H), 7.85 (brt, 2H)

LRMS (FAB) m/e (% abundance) 713.8 [(M+Na)⁺, 50]

What is claimed is:
 1. A method for treating an imbalance between boneproduction and resorption in a host mammal, including a human, themethod comprising the step of administering to the mammal an effectivedose of a compound, or a pharmaceutically acceptable salt thereof, ofthe formula ##STR46## or a compound, or a pharmaceutically acceptablesalt thereof, of ##STR47## where R₁ independently is H, phenyl, C₁ -C₆alkyl substituted phenyl, halogen substituted phenyl, or alkyl of 1 to 6carbons and n is an integer having the values of 1 or 2, and where whenn is 1 the R₁ group is attached to one of the 3 and the 5 positions ofthe 2-furanone, when n is 2 then the R₁ groups are attached to both the3 and 5 positions with the proviso that when n is 1 then R₁ is not H;Y₁is H, alkyl of 1 to 20 carbons, phenyl C₁ -C₂₀ alkyl, C₁ -C₂₀ alkenylcontaining one or more olephinic bonds, PO(OH)₂, PO(OH)OR₂, PO(OH)R₂,PO(OR₂)₂, where R₂ is independently alkyl of 1 to 20 carbons, phenyl, orhalogen substituted phenyl, or C₁ -C₆ alkyl substituted phenyl, furtherY₁ is CO--R₃, CO--OR₃, CONHR₃, SO₂ R₃, SO₂ NHR₃, (CH₂)_(p) --O--R₃, or(CH₂)_(p) --O--(CH₂)_(m) --O--R₃, where p, and m, are integers and areindependently 1 to 20 and R₃ is H, C₁ -C₂₀ alkyl, C₁ -C₂₀ alkenylcontaining one or more olephinic bonds, phenyl, halogen substitutedphenyl, or C₁ -C₆ alkyl substituted phenyl, with the proviso that whenY₁ is CO--R₃, CO--OR₃, and CONHR₃ then R₃ is not hydrogen; Y₂ is analkyl group of 6 to 25 carbons, phenyl, naphthyl, phenyl (C₁-C₂₀)alkyl-, naphthyl (C₁ -C₂₀)alkyl--, C₁ -C₆ alkyl substituted phenyl,halogen substituted naphthyl, C₁ -C₆ substituted naphthyl, and Y₃ is H,alkyl of 1 to 20 carbons, CO--R₄, CO--O--R₄, CO--NH--R₄, PO(OR₄)₂ orPO(OR₄)R₄, where R₄ independently is H, alkyl of 1 to 20 carbons,phenyl, or halogen substituted phenyl, or C₁ -C₆ alkyl substitutedphenyl, with the proviso that when Y₃ is COOR₄ then R₄ is not H.
 2. Amethod of claim 1 where the compound, or a pharmaceutically acceptablesalt thereof, is administered in a daily dose of approximately 0.05 to 0mg per kilogram of body weight of the host to be treated.